2017 ESPEN指南：神经病学临床营养

指南护理与营养· 营养与食品 · 2017

s u m m a r y

Article history: Received 5 September 2017 Accepted 5 September 2017

Keywords: Amyotrophic lateral sclerosis Multiple sclerosis Parkinson's disease Stroke Oropharyngeal dysphagia

Neurological diseases are frequently associated with swallowing disorders and malnutrition. Moreover, patients with neurological diseases are at increased risk of micronutrient de ﬁ ciency and dehydration. On the other hand, nutritional factors may be involved in the pathogenesis of neurological diseases.

Multiple causes for the development of malnutrition in patients with neurological diseases are known including oropharyngeal dysphagia, impaired consciousness, perception de ﬁ cits, cognitive dysfunction, and increased needs.

The present evidence- and consensus-based guideline addresses clinical questions on best medical nutrition therapy in patients with neurological diseases. Among them, management of oropharyngeal dysphagia plays a pivotal role. The guideline has been written by a multidisciplinary team and offers 88 recommendations for use in clinical practice for amyotrophic lateral sclerosis, Parkinson's disease, stroke and multiple sclerosis.

1. Introduction

Numerous neurological diseases demonstrate a major impact on nutrition and the nutritional state of affected patients. In addition to paralysis, immobility, abnormal motor function and various neuropsychological disturbances, it is oropharyngeal dysphagia

that exerts the most profound impact on nutritional intake. For the purpose of this guideline, those conditions with the highest prevalence rates, frequent involvement of dysphagia and malnutrition were chosen. Also, we have considered the conditions in which clinical issues about medical nutrition therapy arise that can be a matter of debate. These are amyotrophic lateral sclerosis (ALS), Parkinson's disease, stroke and multiple sclerosis (MS). To enhance the generalizability of the guideline, a chapter about oropharyngeal dysphagia in general is included as this is a common feature of many neurological disorders.

Especially in rare neurological diseases, the impact of nutritional issues has not been extensively investigated. However, especially if dysphagia is present in these conditions, there is much concern about how to feed the patient and how to stabilize the nutritional state. Thus, data from common diseases have to be cautiously translated to this ﬁ eld.

The oropharyngeal swallow involves a rapid, highly coordinated set of neuromuscular actions beginning with lip closure and terminating with opening of the upper esophageal sphincter. The central coordination of this complex semiautomatic sensorimotor task uses a widespread network of cortical, subcortical and brainstem structures. Many diseases and disorders affecting the central swallowing network or downstream peripheral nerves, muscles and structures may result in an impaired oropharyngeal swallow, i.e. oropharyngeal dysphagia (OD). In addition, aging is also associated with multifactorial changes of swallowing physiology for which the term presbyphagia has been coined. OD broadly affects respiratory safety due to the increased risk of aspiration, and swallowing ef ﬁ cacy leading to the impeding danger of insuf ﬁ cient nutrition and hydration [1] . Within the ICD 10 catalogue, dysphagia is referenced with the code R13. More speci ﬁ c, R13.0 denominates the inability to swallow at all, R13.11 stands for oral phase dysphagia, R13.12 for oropharyngeal dysphagia and R13.13 for pharyngeal dysphagia.

OD is one of the most frequent and life-threatening symptoms of neurological disorders [2] . Swallowing impairment is observed in at least $50\%$ of patients with ischemic or hemorrhagic stroke [3 e 5] . These patients have a three-fold increased risk of developing early aspiration pneumonia, and their mortality is signi ﬁ cantly higher than in non-dysphagic stroke patients [4] . Similar data have been published for severe traumatic brain injury , in which the incidence of clinically relevant dysphagia is approximately $60\%$ [6] . In this patient population, the occurrence of dysphagia is associated with signi ﬁ cantly longer arti ﬁ cial respiration and prolonged arti ﬁ cial nutrition [7] . In patients with Parkinson's disease , neurogenic dysphagia is also a major risk factor for the development of pneumonia, the most frequent cause of death in this patient group [8] . In addition, swallowing disorders in these patients typically lead to major and long-term reduction in quality of life (QoL), insuf ﬁ cient medication intake and pronounced malnutrition [9] . In multiple sclerosis, dysphagia occurs in more than one third of patients [10] and increases the risk for aspiration pneumonia and death in particular in the late stages of the disease [11] . Up to $30\%$ of all ALS patients present with swallowing impairment at diagnosis [12] and practically all ALS patients develop dysphagia as the disease progresses. In $15\%$ of all cases, myasthenia gravis manifests itself with swallowing impairment. As the illness progresses, over $50\%$ of all patients are affected, and in more than $50\%$ of cases, a myasthenic crisis is preceded by dysphagia [13] . Patients with inﬂ ammatory muscle disorders are also often subject to swallowing impairment. The frequency is approximately $20\%$ in dermatomyositis , $30{-}60\%$ in polymyositis , and between 65 and $86\%$ in inclusion body myositis [14] . Finally, dysphagia also represents an important diagnostic and therapeutic challenge in the intensive care unit . Regardless of the primary illness, $70{-}80\%$ of patients requiring prolonged mechanical ventilation present, at least temporarily, with signi ﬁ cant swallowing impairment and aspiration after weaning from arti ﬁ cial respiration, predominantly due to a critical illness polyneuropathy [15] . This impairment not only necessitates prolonged arti ﬁ cial nutrition, but is also linked to serious complications, such as pneumonia and the necessity for reintubation. In addition, it is an independent predictor of increased mortality [16] . Apart from these speci ﬁ c disorders, increasing age itself is a wellestablished risk factor for OD. The prevalence of this condition among independently living older persons is $16\%$ in the 70 e 79-year

old group and $33\%$ in the ${\ge}80$ -year old group. Furthermore, $51\%$ of institutionalized older persons are affected and up to $47\%$ of frail elderly patients hospitalized for acute illness are diagnosed with OD. Consequences of OD in the elderly are devastating and include aspiration pneumonia, dehydration and malnutrition [17] .

2. Methodology

2.1. Methodology of guideline development

The guideline was developed by an expert group of the disciplines: Clinical nutrition, Neurology, Geriatrics, Dietetics and Intensive Care, from 9 countries. All members of the working group had declared their individual con ﬂ icts of interest according to the rules of the International Committee of Medical Journal Editors (ICMJE).

Based on the standard operating procedures for ESPEN guidelines and consensus paper [18] we decided on topics to be covered at the start of the guideline process through several rounds of discussion and modi ﬁ cation. Initially, the guideline was focused on chronic neurological diseases including ALS, PD and MD, but after a meeting in September 2014, we decided to broad the scope of the guideline and to include stroke, in order to address the main neurological diseases. To initiate the literature searches, we designed 41 speci ﬁ c clinical questions, in a PICO format when appropriate. The working process was supervised and monitored by the ESPEN Guideline of ﬁ ce for methodological quality. On the internet portal www.guideline-services.com , the draft and the literature was accessible at any time exclusively for members of the working group. After the literature search, evaluation and grading of the evidence, the guideline development group drafted a total of 88 recommendations. The draft was send to the ESPEN members via email in a ﬁ rst Delphi round in July 2016. We received a strong consensus (agreement of ${\tt>}90\%$ ) in $91.8\%$ of recommendations, consensus (agreement of $75{-}90\%$ in $8.1\%$ of recommendations. None of the recommendations reached an agreement lower than $75\%$ . The recommendations with an agreement lower than $90\%$ were discussed in an ESPEN guidelines consensus conference, which was performed on September 18th during ESPEN Congress 2016 in Copenhagen. After the voting, all the selected recommendations were discussed; modi ﬁ cations were included, and reached a consensus greater than $85\%$ .

2.2. Search strategy

Before starting with the classical literature search, we explored and identi ﬁ ed relevant published valid guidelines (German Guidelines-DGEM, NICE, SIGN ). After this ﬁ rst review, we … searched the main Bibliographic Databases (Pubmed, EMBASE, and the Cochrane Library) for recent systematic reviews and metaanalyses that answered our clinical questions. In their absence, we looked for other indirect systematic reviews and meta-analyses and, in the absence of these, we looked for comparative studies, whether randomized or not. Also an updated literature search was conducted to retrieve further comparative studies. The screening was performed by reading the abstract, followed by the entire article when necessary. Literature search was conducted for the last 10 years, until June 2016, although the working group was allowed to consult some highly relevant previous articles.

Due to the complexity of the literature search for all the questions assessed, we show an example of the search strategy for the clinical question 35 ( Table 1 ).

The classi ﬁ cation of the literature according to evidence levels and the grades and forms of recommendation were performed

Clinical Question 35. Does tube feeding compared to other feeding strategies lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with severe dysphagia? P: patients with acute stroke I: enteral nutrition or enteral feeding or tube feeding C: stroke patients with ONS or with oral texture-modi ﬁ ed diet alone O: complications, length of stay, infectious complications, poor outcome, mortality, energy intake, body weight, quality of life. First search: Two guidelines on nutritional support in stroke patients have been published in 2013 [DGEM Guidelines [19] and Royal College of Physicians [20] ], both with literature review covering data until December and October 2011, respectively. One systematic review of the literature was published in 2012 [21] including a review of the literature until July 2011. Second search: Strategy was dated from December 2011 until June 2016: Stroke [MeSH] OR Stroke [Title/Abstract] AND enteral feeding [Title/Abstract] 24 articles retrieved. 18 non-relevant by reading title 2 non-relevant after reading abstract 1 review article 3 relevant articles selected. None intervention study, all were observational studies.

following the Scottish Intercollegiate Guidelines Network (SIGN) grading system [22] , updated in 2014 ( Tables 2 and 3 ).

Some of the recommendations of these guidelines were developed on the basis of expert opinion because we found no evidence or only low quality evidence in the literature.

In case of inconsistent data between different studies regarding one clinical question, a consensus within the group was achieved.

The manuscript was reviewed and align with the recent ESPEN Guidelines on de ﬁ nitions and terminology in clinical nutrition [23] .

3. Amyotrophic lateral sclerosis (ALS)

ALS is a complex neurodegenerative disorder characterized by progressive loss of motor neurons, resulting in progressive atrophy of skeletal muscles, including the respiratory muscles. The etiology of ALS is multifactorial. Increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, in ﬂ ammation and apoptosis have been implicated as causative factors in neuronal insult that initiated the pathogenesis of the disease [24] . In ALS patients, malnutrition is common. The following factors has been associated with the risk of malnutrition [25] :

- The degeneration of bulbar neurons manifests as dif ﬁ culty in chewing, oral preparation, time required to complete a meal, and dysphagia.

Table 1 Example of the search strategy.

Table 2 Levels of evidence (SIGN grading system) [22] .

|1++| High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. | |---|---| || High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. | |1+| Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort studies. | || Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort studies. | |2++|| || High quality systematic reviews of case control or cohort studies. High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is | ||| |ＺIT| Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal | ||| |N|Case control or cohort studies with a high risk of confounding or| ||bias and a significant risk that the relationship is not causal| ||Non-analytic studies, e.g. case reports, case series| ||Expert opinion|

Table 3 Grades and forms of recommendations (SIGN grading system) [22] .

|a. Grades of recommendation||| |---|---|---| || At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or || |||| || A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results || |||| || A body of evidence including studies rated as 2++, directly applicable to the target population; or || || A body of evidence including studies rated as 2+, directly applicable to the target population, and demonstrating overall consistency of results; O1 || || O1 Extrapolated evidence from studies rated as 1++ or 1+ Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2++ or 2+ Good practice points/expert consensus: Recommended best practice based on the clinical experience of the guideline development group || |GPP||| |GPP||| |b. Forms of recommendation||| |Judgment|Judgment|| | Undesirable consequences clearly outweigh desirable consequences |Strong recommendation against|| |||| | Undesirable consequences probably outweigh desirable | Conditional recommendation against || |consequences||| |Balance between desirable and|| Recommendation for research and possibly conditional | ||undesirable consequences is|| |closely balanced or uncertain| recommendation for use restricted to trials || ||Conditional recommendation for|| | Desirable consequences probably outweigh undesirable consequences ||| | Desirable consequences clearly outweigh undesirable |Strong recommendation for|| |||| |consequences|||

- Anorexia is common; it is usually attributed to psychosocial distress, depression, and polypharmacy. - The weakness of the abdominal and pelvic muscles, limitation in physical activity, the self-restraint of ﬂ uids and a diet low in ﬁ ber can cause constipation, which indirectly may impairs intake of food. - Despite the reduction in lean body mass, ALS patients can have some increased energy requirements due to increased work of breathing, lung infections and other factors not yet well established. - Cognitive dysfunction ${\it20-50\%}$ of cases), mainly frontotemporal dementia.

ALS presents in two main different forms: bulbar progressive paresis (bulbar onset, $25{-}35\%$ of patients) or spinal motor neuron injury (limb onset or peripheral onset). Almost $80\%$ of ALS patients with bulbar onset will develop dysarthria and dysphagia. In a spinal or peripheral onset of the disease muscle weakness is the main symptom. Patients with bulbar onset and older age have the shortest life expectancy. Mean survival of ALS is 3 e 5 years, with $5\%{-}10\%$ living longer than 10 years [26] . Eventual respiratory failure and malnutrition with dehydration are the primary cause of death.

3.1. Clinical Question 1: Is nutritional status a prognostic factor for survival in ALS patients?

Recommendation 1:

At diagnosis, a complete nutritional assessment is recommended in ALS patients, including Body Mass Index (BMI),

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

weight loss over time and lipid status. Body composition analysis using DEXA or BIA with validated formula should be performed if available.

Grade of recommendation: B e strong consensus ( $\bf{100\%}$ agreement)

Recommendation 2:

During the follow-up, nutritional status assessment (BMI, weight loss) is recommended over time, in order to detect early malnutrition and plan for treatment. Body composition analysis should be performed if available.

Grade of recommendation: B e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

The effect of nutritional status on the prognosis of patients with ALS depends on which parameter is being evaluated and the time when it is evaluated.

At diagnosis: With regard to the BMI and loss of BMI, BMI baseline was associated with survival (Hazard Ratio $[\mathrm{HR}]=0.94$ $[95\%$ CI: 0.90 e 0.98]; $\mathsf{p}=0.005)$ ), $(\mathrm{HR}=0.95$ $[95\%$ CI: 0.91 e 0.99]; ${\tt p}=0.01$ ) [26,27] . For a loss of 1 BMI point the risk of death was of $9{-}23\%$ higher $\mathrm{HR}=1.09$ [95% CI: 1.03 e 1.15]; $\mathsf{p}=0.004\$ $\mathrm{{,HR=1.23}}$ $[95\%$ CI: 1.07 e 1.41]; $\mathsf{p}=0.003)$ ) [28,29] .

Regarding the initial weight loss, patients losing more than $5\%$ of their weight compared to usual weight had 2 times risk of death $\mathbf{\tilde{HR}}=1.92$ $[95\%$ con ﬁ dence interval [CI]: 1.15 e 3.18]; ${\tt p}=0.01$ ) [28] . Moreover after adjusting for known prognostic factors (age, gender, form of bulbar onset, diagnosis delay, amyotrophic lateral sclerosis functional rating scale [ALSFRS], manual muscular testing, forced vital capacity [FVC]) for a weight loss of $5\%$ at diagnosis compared to usual weight the risk of death was increased by $14{-}30\%$ $\mathrm{HR}=1.14$ $[95\%$ CI: 1.05 e 1.23 ]; $\mathsf{p}=0.002.$ ), $\mathbf{\tilde{HR}}=1.30$ $[95\%$ CI: 1.08 e 1.56]; $\mathsf{p}=0.006\$ [28,29] . In addition, weight loss of $10\%$ at diagnosis entailed an increase in the risk of death of $45\%$ $\mathrm{HR}=1.45\%$ $[95\%$ CI: 1.06 e 1.99]; $\mathsf{p}=0.046)$ ) [29] .

Malnutrition at diagnosis was not associated with survival [28,29] .

Focusing on bioelectric impedance phase angle (PA) and body composition, initial higher PA reduced the risk of death of $20\%$ $\mathrm{{HR}}\,{=}\,0.80$ [95% CI: 0.65 e 0.98]; $\mathsf{p}\,{=}\,0.003\,,$ ) [27] . An increased risk of death of $29\%$ was found for a loss of 1 degree of PA ( $\mathrm{HR}=1.29$ [95% CI: 1.02 e 1.63]; $\mathsf{p}=0.003\$ ) [28] . There was no association between survival and body composition (fat-free mass [FFM]) [26,28] .

Hypermetabolism (resting energy expenditure [REE] measured ' REE calculated )/REE calculated $>10\%$ ), was not association with survival [30] .

A decrease of serum albumin was a risk of death factor (men: $\mathrm{HR}=1.39$ [95% CI: 1.05 e 1.90]; ${\tt p}\!=\!0.02$ and women: $\mathrm{HR}=1.73$ $[95\%$ CI: 1.35 e 2.39]; ${\tt p}=0.001$ ) [31] .

Looking at serum lipids, a decreased LDL/HDL-cholesterol ratio increased the risk of death by $35\%$ $\mathbf{\dot{H}R}=1.35$ $[95\%$ CI: 1.08 e 1.69]; $\mathsf{p}\;=\;0.0075$ ) [32] . Inversely, a higher LDL/HDL-cholesterol ratio decreased the risk of death by $17\%$ ( $\mathrm{HR}=0.83$ $[95\%$ CI: 0.71 e 0.92]; $\mathtt{p}=0.027)$ ) [31,33] . In addition, a high levels of total cholesterol, LDL-cholesterol and triglycerides at diagnosis were associated with better survival [27,31,33,34] .

During the follow-up: Malnutrition, was an independent prognostic factor for survival with a risk of death increased by 2.2 e 7.4 fold in case of malnutrition ( $.95\%$ CI: 1.09 e 4,25; ${\tt p}=0.01$ ), $\mathbf{\Delta}[95\%$ CI: 1.7 e 32.1; $\tt p\,<\,0.011$ ) respectively, (after adjusting for ALS-form, disease duration prior to consultation, duration of riluzole treatment, age at onset, and presence of a gastrostomy) [28,35] . On U

shaped curve a higher percentage of death was found in case of malnutrition and class III obesity [36] .

Regarding the weight loss, a weight loss over $20\%$ after the gastrostomy was associated with an increased risk of death $\mathrm{HR}=1.04$ $[95\%$ CI: 1.02 e 1.06]; ${\tt p}=0.01$ ) [37] . In addition, each weight loss of $5\%$ was associated with an increased risk of death of $34\%$ ( $\mathbf{\dot{H}R}=1.34$ $[95\%$ CI: 1.18 e 1.51]; $\mathsf{p}<0.0001)$ [28] .

With regard to the variation of BMI, each loss of 1 point of BMI was associated with increased risk of death of $24\%$ ( $\mathrm{HR}=1.24$ $[95\%$ CI: 1.13 e 1.36]; $\mathsf{p}<0.0001\big]$ ) [28] . A loss of more than 2.5 points of BMI had a shorter survival with 2.7 times risk of death $\mathbf{\tilde{HR}}=2.74$ $[95\%$ CI: 1.47 e 5.13]; ${\tt p}=0.001$ ) [38,39] . Inversely, every gain of 1 point of BMI the risk of death was reduced by $14\%$ ( $\mathbf{\dot{H}R}=0.86$ $[95\%$ CI: 0.80 e 0.93]; $\mathbf{p}=0.0001$ ) (after adjustment for age, cardiovascular disease, beginning of symptoms and FVC) [36] .

Regarding the PA and body composition, an increase of risk of death for each loss of 1 degree of PA ( $\mathrm{HR}=1.68$ [95% CI: 1.27 e 2.23]; $\mathsf{p}\,{=}\,0.0003)$ ) [28] . PA and FFM decrease were associated with shorter survival, regardless of weight loss [39] . In addition, patients with higher fat mass (FM) during the disease had a signi ﬁ cantly increased survival, for an increase of $2.5~\mathrm{kg}$ of FM the risk of death was reduced by $10\%$ $\mathbf{\tilde{HR}}=0.90$ [ $\mathbf{\i}.95\%$ CI: 0.83 e 0.96]; $\mathsf{p}=0.003)$ [28] . Bioelectrical impedance (BIA) with validated formula compared to dual-energy X ray absorptiometry (DEXA) is a simple, fast and available method to assess body composition of ALS patients in clinical practice [40] . Although the gold standard to assess the body composition is DEXA, this method is more expensive, less available and rarely used on ALS [41] .

In summary, nutritional status (malnutrition, BMI, weight loss, BMI loss, bodycomposition, and lipid status) is a prognostic factor for survival in Motor Neuron Disease-ALS patients. At diagnosis, weight loss, BMI, PA and lipids status are prognostic factors for survival. During the follow up, malnutrition, weight loss, BMI loss and body composition are prognostic factors for survival. Nutritional risk assessment should be encouraged, using a validated malnutrition screening tool. See supplementary data for Clinical Question 1 .

3.2. Clinical Question 2: What are nutritional requirements in ALS patients?

Recommendation 3:

Energy requirements in non-ventilated ALS patients should be estimated if indirect calorimetry is not available. Calculations should be estimated as approx. 30 kcal/kg body weight depending on physical activity, and adapted to weight and body composition evolution.

Degree of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Determination of nutritional requirements in ALS patients requires estimation of their total energy expenditure (TEE), which consists of the sum of the energy expenditure related to resting energy expenditure (REE), food-related thermogenesis and physical activity. The gold standard to measure REE is indirect calorimetry. However, it is generally not available in clinics, leading to the use of equations to estimate REE. Mean predicted energy expenditure generally corresponds to measured REE at a population level [42] . However, a study including 34 ALS patients showed that REE estimated by the Harris e Benedict equation is not valid compared to indirect calorimetry because of limits of agreement ranging from ' 677 to $+591$ kcal/day, leading to under- or overfeeding in the majority of patients [43] . The limited validity of equations to

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

estimate REE in individual ALS patients has been later con ﬁ rmed [44,45] . Kasarksis et al. also found a large variation of TEE measured by doubly-labeled water in 80 ALS patients and reported that TEE corresponds to REE in some patients but greatly exceeds REE in others [44] . This suggests not only that REE is variable but also energy expenditure related to physical activity.

Thus, as energy expenditure in ALS patients cannot be properly calculated in clinical routine, nutritional requirements have not been clearly determined. Some authors suggest relying on fat-free mass-adjusted REE, estimated around $34~\mathrm{kcal/kg}$ body weight in ALS patients breathing spontaneously [42] . Other suggest to use the Harris e Benedict equation adjusted for correction factors to evaluate nutritional requirements and then to adapt the intakes according to evolution of weight and body composition [46,47] .

There is insuf ﬁ cient data to perform any recommendations about protein requirements for ALS patients, and common determining factors should be considered: age, kidney function, degree of stress.

Recommendation 4:

Non-invasive ventilation is generally associated with a lower REE than spontaneous breathing or predicted by the Harris e Benedict equation. In the absence of indirect calorimetry, energy requirements should be estimated as 25 e 30 kcal/kg body weight or using the Harris e Benedict equation, and adapted following the evolution of body weight and the clinical situation.

Degree of recommendation: 0 e strong consensus $\mathbf{\{95\%}}$ agreement)

Commentary:

A recent study shows that non-invasive ventilation reduces REE by $7\%$ in 16 ALS patients compared to spontaneous breathing, due to decreased activity of inspiratory neck muscle [48] . Siirala et al. showed that measured REE was $33.6\%$ lower in ﬁ ve ALS patients under intermittent positive pressure ventilation, than the mean REE estimated by 5 different predictive equations [49] . Shimitzu et al. also found a reduced measured REE in 11 mechanically ventilated patients compared to REE estimated by the Harris e Benedict equation [50] . In contrast with these studies, Sherman et al. showed a higher measured REE than predicted by the Harris e Benedict equation in 18 ALS patients under mechanical ventilation. They hypothesized that these results were due to higher cytokine secretion, more fasciculations or refeeding, as many of these patients had been hospitalized for Percutaneous Endoscopic Gastrostomy (PEG) placement [43] . Ichihara et al. measured TEE by doubly-labeled water in 10 bedridden Japanese ALS patients who were under $24\,\mathrm{h}$ tracheostomy positive pressure ventilation [51] . They reported that the ratio of TEE over fat-free mass derived from total body water measurement was $35\pm5.5~\mathrm{kcal/kg/day}$ , thus similar to the value found in non-ventilated patients. In 3 patients, they measured REE by indirect calorimetry and showed that the ratio of TEE over REE was 1.05, thus that energy expenditure related to physical activity was negligible. See supplementary data for Clinical Question 2 .

3.3. Clinical Question 3: Should ALS patients gain weight or not?

Recommendation 5:

In ALS patients, weight loss is detrimental for survival, but whether oral or EN should aim at weight stabilization or weight gain has not been clari ﬁ ed and may depend on baseline nutritional state. Weight gain should be recommended in patients with a baseline body mass index (BMI ${\bf<}25.0~\,{\bf k g/m^{2}}$ ), weight stabilization in those with a BMI between 25 and 35 $\mathbf{kg}/\mathbf{m}^{2}$ , and

weight loss in patients with a $\mathbf{B M I\;>\;35\;\;k g/m^{2}}$ in order to improve passive and active mobilization.

Degree of recommendation: GPP e strong consensus (95% agreement)

Commentary:

Several studies have shown that a weight ${\log}s>5{-}10\%$ habitual weight or a BMI below $18.5\,\mathrm{kg}/\mathrm{m}^{2}$ at the time of diagnosis has been associated with decreased survival [35,39,52] . Furthermore, weight loss ${\geq}10\%$ at the time of PEG placement was also associated with an increased mortality in multivariate analysis (RR 4.18, 95 %CI 2.72 e 6.42) [53] . This raises the question whether increasing body weight is bene ﬁ cial once ALS has been diagnosed [54] .

Nutrition therapy (oral nutrition supplementation and enteral nutrition) may stabilize body weight in ALS patients [55,56] , but no studies have evaluated whether this intervention is associated with an improved survival. Based on several studies, the American Academy of Neurology states that EN by PEG may improve survival in ALS patients [55] . In contrast, the guidelines of the European Federation of Neurological Societies report no convincing evidence for an improved survival with EN by PEG [57] . See supplementary data for Clinical Question 3 .

3.4. Clinical Question 4: What is the prevalence and natural history of oropharyngeal dysphagia in ALS? Speci ﬁ c prevalence of nutritional and respiratory complications in patients with ALS: malnutrition and aspiration pneumonia

Recommendation 6:

Due to the high prevalence and the impact on nutritional status and risk for respiratory complications, dysphagia screening is recommended in every ALS patient.

Grade of recommendation: B e strong consensus (100% agreement)

Recommendation 7:

Screening for malnutrition (BMI, weight loss) is recommended at diagnosis and during the follow-up every 3 months. Grade of recommendation: B e strong consensus $\mathbf{\{95\%}}$ agreement)

Commentary:

Natural history of oropharyngeal dysphagia : Oropharyngeal dysphagia is a severe and invalidating symptom for ALS patients [58] . Swallowing disorders disturb the ability to move food or liquids safely and ef ﬁ ciently from the mouth through the pharynx into the esophagus. The weakness of muscles involved in the oral and preparatory phase of deglutition leads to a poor lip sail with drooling and trap food particles in the buccal sulcus [12,59] . Weakness of masticatory muscles leads to a poor chewing and impairs the ability to form a normal food bolus, and weakness of tongue muscles impairs the tongue ability to propel the food bolus. During the pharyngeal phase, a reduction of the soft-palate closure leads to re ﬂ ux of food and liquid into the nose. At last, alteration of pharyngeal peristalsis leads to a high risk of aspiration during swallowing due to incomplete epiglottic closure. Dysphagia is more often found in patients with bulbar onset but patients with spinal onset can also develop swallowing disorders [58] . Nearly all patients with ALS manifest bulbar involvement in advanced disease. Swallowing disorders affect food intake, with an increase of meal time and asthenia during and after the meal [12] . During ALS,

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

swallowing changes may occur in 5 stages: 1) normal eating habits; 2) early eating problems such as dif ﬁ culty of chewing; 3) dietary consistency changes; 4) a need for tube feeding and 5) nothing by the mouth [59,60] . Consequently, these disorders will cause an alteration of nutritional status with weight loss and a risk to develop a state of malnutrition. At short, medium or long term, worsening swallowing disorders and nutritional status put the indication of arti ﬁ cial nutrition by feeding tubes, gastrostomy is preferable [57] . Dysphagia can lead not only to aspiration pneumonia and malnutrition, but can also alter quality of life, with anxiety during the meal for patients and their caregivers [57,58,61] .

Prevalence of dysphagia: The prevalence of dysphagia is variable in different studies depending on the evaluation method (patient interview, bedside examinations, swallowing scale, videoﬂ uoroscopic evaluation, endoscopic evaluation), the time of disease progression and the predominant type (spinal/bulbar) of the evaluated patients. With endoscopic evaluation, $47.8\%{-}72.7\% $ of dysphagia was found mainly in patients with bulbar form [58,62,63] . With video ﬂ uoroscopic evaluation of swallowing, $75\%$ of patients had dysphagia [64] . Closed to $48\%$ of dysphagia were found (through bedside examinations and the Dysphagia Limits amounts of $20~\mathrm{{ml}}$ or more at a time) [65,66] . With clinical assessment, $6\%$ of isolated dysphagia and $15\%$ of dysphagia and dysarthria were found ( $35\%$ of bulbar form) [67] . The presence of dysphagia after patient interview was found in $85.7\%$ of cases in bulbar form, $42.9\%$ in upper limbs form and in $71.4\%$ in lower limbs form $_{(33,4\%)}$ [68] . With a same assessment $34.7\%$ of dysphagia was found $(21.4\%$ of bulbar form) [69] . Using a swallowing scale $41.1\%$ to $70.0\%$ of swallowing disorders were found [66,70] . Dysphagia as an initial symptom of ALS was found in $6.2\%$ of patients [69] .

Prevalence of malnutrition: At diagnosis, with BMI criteria $(<\!18.5~\mathrm{kg}/\mathrm{m}^{2})$ ) malnutrition was found in $0\%–1.1\%$ , $10.1\%$ $\zeta{<}20~\mathrm{kg}/$ $\mathrm{m}^{2\cdot}$ ) and 8.7% e 13.0% ${\langle<}18.5\;\mathrm{kg}/\mathrm{m}^{2}$ if age < 70 years and ${<}21\;\mathrm{kg}/\mathrm{m}^{2}$ if $\mathtt{a g e>}70$ years) [26,28 e 30,38,72] . With weight loss criteria $(>\!10\%)$ malnutrition was found in $21.0\%$ [29,70] . During the follow-up, with BMI criteria $(<\!18.5~\mathrm{kg}/\mathrm{m}^{2})$ ) $2.1\%{-}20.1\%$ , $(<\!20\mathrm{~kg}/\mathrm{m}^{2})$ $16.1\%{-}26.4\%$ and $(<\!18.5~\mathrm{kg}/\mathrm{m}^{2}$ if age ${<}70$ years and ${<}21~\mathrm{kg}/\mathrm{m}^{2}$ if age > 70 years) $7.5\%{-15.2\%}$ of patients were malnourished [28,35 e 37,44,64,72,77] . With weight loss criteria (weight $_{10s s>10\%}$ ) $25.0\%$ to $48\%$ and $24.5\%$ (weight loss ${>}20\%$ ) of malnutrition was found [72 e 74] . At the time of gastrostomy $17.8\%$ $^{'<18.5\mathrm{~kg}/\mathrm{m}^{2})}$ and $27.4\%–53.0\%$ $(<\!20\;\mathrm{kg}/\mathrm{m}^{2})$ of patients were malnourished [75,76] .

Prevalence of aspiration pneumonia: $13\%$ of aspiration pneumonia was found [73] . In a post mortem study of the cause of death, aspiration pneumonia was found in $11.4\%$ of cases [74] . However, in this study, $41\%$ of patients died because of a bronchopneumonia, and another $9\%$ of patients due to respiratory failure.

In summary, dysphagia is found in $6.2{-}85.7\%$ of ALS patients $(48.1–85.7\%$ in bulbar form and $41.1\substack{-71.4\%}$ in spinal form). At diagnosis, malnutrition is present in $_{0-21\%}$ depending on the criteria used to evaluate and in $7.5{-}53\%$ during the follow up. Few studies assessed the prevalence of aspiration pneumonia, and this prevalence is close to $15\%$ . Considering the median survival of 18 e 28 months and the risk of impaired nutritional status with dysphagia, follow up every 3 months is recommended [28,29,66] . See supplementary data for Clinical Question 4 .

3.5. Clinical Question 5: At what stage of the disease do we need to screen for dysphagia in ALS patients?

Recommendation 8:

We recommend that screening for dysphagia should be performed in all ALS patients, both at diagnosis and during follow up, as part of a comprehensive clinical and neurological

evaluation. The frequency of dysphagia clinical evaluation at follow-up should depend on the presence and the progression of clinical signs. In general, a 3 months frequency can be recommended.

Grade of recommendation: GPP e strong consensus (91% agreement)

Commentary:

Several studies revealed some alterations in the swallowing capacity in ALS patients at an early stage of the disease, even in the absence of bulbar symptoms. Thus, both symptoms and clinical signs of dysphagia should be evaluated, as part of a comprehensive clinical and neurological evaluation, in every ALS patient, at the time of diagnosis and during the following clinical evaluations. The frequency of dysphagia clinical evaluation at follow-up should depend on the presence and the progression of clinical signs. In general, a 3 months frequency evaluation can be recommended [55] .

Clinical severity scales of ALS such as “ ALS functional rating scale-revised ” (ALSFRS-R) or ALS Swallowing Severity Scale (ALSSS) include data regarding the presence or absence and the severity of dysphagia [75] . These scales are usually based on patient's symptoms. A new scale for dysphagia in patients with progressive neuromuscular diseases, including motor neuron disease (MND), has recently been developed [76] .

Clinical assessment of dysphagia should include evaluation of lip closure and evidence of saliva pooling, tongue strength, mobility and tone, chewing capacity, palatal movement in response to tactile stimulation, the quality and strength of the cough as well as phoniatric function. Facial and lateral jaw movements are usually normal in the early stages of ALS [12] . A swallow test can also be performed [77] . Volume-Viscosity Swallowing Test (V-VST) has been shown to have a high sensitivity to identify patients at risk of aspiration. Instrumental assessment of dysphagia, video ﬂ uoroscopy (VFS) or ﬁ beroptic endoscopic evaluation of swallowing (FEES) is usually performed according to local protocols, in patients with symptoms of dysphagia. There are no studies comparing different protocols in ALS patients. See supplementary data for Clinical Question 5 .

3.6. Clinical Question 6: Are there speci ﬁ c methods for screening and clinical diagnosis of oropharyngeal dysphagia in ALS?

Recommendation 9:

There are no speci ﬁ c methods available to screen or clinically evaluate dysphagia in ALS patients, and general screening and evaluation methods for neurological disorders are appropriate. Structured questionnaires, water swallow tests and volumeviscosity swallow test can be applied. Instrumental techniques (video ﬂ uoroscopy, video ﬂ uoromanometry and ﬂ exible endoscopic evaluation of swallowing) allow detecting early signs of dysphagia in ALS patients.

Grade of recommendation: B e strong consensus (96% agreement)

Commentary:

There are no clinical studies on any speci ﬁ c method for screening and clinical diagnosis of OD in ALS patients. Structured questionnaires for screening of OD, such as EAT-10, have been tested in ALS patients. One study has evaluated the discriminatory ability of EAT-10 to identify patients with unsafe airway protection during swallowing. Seventy ALS patients, with a mean disease duration of the disease of 17.9 months (range 2 e 72, DS 13), ALSFRSR score of 34.8 (range 16 e 47, DS 7.9) completed an EAT-10 questionnaires and underwent a video ﬂ uoroscopic evaluation of

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swallowing. In this study, EAT-10 offered high discriminant ability to identify ALS patients who aspirate (sensitivity $86\%$ , speci ﬁ city $76\%$ negative predictive value $95\%$ ) [78] . Water swallow tests and the V-VST [79] has also been used for clinical screening and evaluation of OD in ALS patients. Twenty patients were evaluated in one study. In comparison with video ﬂ uoroscopy, the sensitivity of VVST to detect OD in ALD patients was $92\%$ , and speci ﬁ city $80\%$ $\mathbf{\dot{p}}=0.007)$ . The evaluation of voluntary cough air ﬂ ow can also differentiate safe and unsafe swallowing in ALS patients [80] .

Video ﬂ uoroscopy is considered one of the main diagnostic tools for the clinical evaluation of OD in ALS patients [55] . The protocol includes the use of different consistencies and volumes of contrast bolus. VFS can contribute to examine the different phases of the swallowing process as well as the presence of oral or pharyngeal residue. It can identify silent aspirations and can evaluate the effect of compensatory postures in ALS patients with dysphagia [81] . Several cross-sectional and cohort studies have been published that assessed the role of VFS in identifying swallowing abnormalities in ALS patients [82 e 86] . VFS can also be performed in conjunction with pharyngeal manometry and can show alterations even in ALS patients with normal VFS [87,88] . Manometry in ALS patients have revealed low tongue driving forces and pharyngeal contraction amplitudes and normal relaxation of the upper esophageal sphincter [89] . Data have shown a decrease of the pharyngeal force with the progression of the disease [90] .

Fiberoptic endoscopic evaluation of swallowing (FEES) is a bedside clinical evaluation that can be considered an ef ﬁ cient method in the assessment of OD [78] . FEES can identify impaired chewing, tongue muscle de ﬁ cit, velo-pharyngeal closure competence, laryngeal morphology and motility, and cough re ﬂ ex sensitivity and to detect eventual pharyngeal residues [91] . FEES effectivity has been evaluated in ALS patients. In a cross-sectional historical cohort study including 11 patients, of which $72.7\%$ complained of dysphagia, oral or pharyngeal alterations were observed in all studied individuals [92] . In a longitudinal study in 49 ALS patients, the presence of chewing de ﬁ cit could predict dysphagia at 12 months follow-up [62] .

Ultrasonography can also be used in the clinical evaluation of OD in ALS patients, as it can identify tongue thickness alterations [58] , and has a high sensitivity to identify early alterations in the oral phase of the swallowing process, such as abnormal bolus position or reduced or disorganized lingual movement [93] .

Oropharyngoesophageal scintigraphy permits a functional and semi quantitative evaluation of the various stages of swallowing and has been used in ALS patients [94] .

In summary, there are no speci ﬁ c methods for the screening and clinical diagnosis in ALS patients. Both EAT-10 and volume-viscosity swallow test have been shown to have high sensitivity and speciﬁ city in the identi ﬁ cation of patients with unsafe swallow. Videoﬂ uoroscopy, video ﬂ uoromanometryand FEES can detect early signs of dysphagia in ALS patients. Other methods, such as ultrasound or scintigraphy have been also employed in ALS patients. Most studies included a limited number of patients, with different clinical characteristics and time from diagnosis. More studies are needed to further evaluate the clinical ef ﬁ cacy of these techniques in ALS patients. See supplementary material for Clinical Question 6 .

3.7. Clinical Question 7: What are the speci ﬁ c and frequent video ﬂ uoroscopic (VFS) signs in patients with ALS?

Recommendation 10:

Video ﬂ uoroscopy study can detect early signs of dysphagia in ALS patients, and should be recommended in the clinical evaluation of dysphagia in these patients at diagnosis of the disease.

Grade of recommendation: GPP e strong consensus (95% agreement)

Commentary:

Video ﬂ uoroscopy can evaluate the physiopathological alterations in the swallowing process and detect silent aspirations in patients with OD. A penetration/aspiration scale has been proposed [95] .

Several studies have evaluated these alterations in ALS patients. Initial studies described that the oral phase of swallowing was the mostcompromised,followedbythepharyngealphase [82] .Onestudy evaluated 23 ALS patients with clinical dysphagia, according to ALS Severity Score (ALSSS) [83] . Aclinicalevaluation of ODwas performed using VFS, FEES and manometry. The most prevalent VFS ﬁ ndings in these patients were oral stasis of residual barium (9/13), piecemeal swallowing (6/13), incomplete relaxation of upper esophageal sphincter and decreased pharyngo-esophageal motility. Aspiration was observed in $6/13$ patients. Other studies have also observed an earlyalteration inoral phaseof the swallowingprocessinALS patients with mild dysphagia [87] . In a study performed in 23 ALS patients, swallowing alterations were present in $66,7\%$ of patients with “ normal eating habits ” on the ALSSS scale, $33\%$ in the oral phase and $75\%$ in the pharyngeal phase (especially pharyngeal contraction reduction) [84] . In ﬁ ve patients $(41.6\%)$ , bolus stasis in the pharynx was observed and induced episodes of post-swallowing penetration.

In a longitudinal study in 72 examinations in 50 ALS patients, delayed bolus transport from the oral cavity to the pharynx, and bolus stasis in the pyriform sinus were seen in about half of the patients with no bulbar symptoms [84] . Upper esophageal sphincter opening was preserved in 2/3 of patients with more than 24 months of disease progression. Bolus holding in the oral cavity, constriction of the pharynx and elevation of the larynx worsened progressively over time. The frequency of aspiration also increased over time.

One recent study has evaluated the VFS signs of dysphagia at the initial diagnosis of ALS in 19 patients [86] . Six patients presented only bulbar disorder and 8 presented a combination of bulbar and extremity symptoms. Fourteen physiological components of swallowing and the presence or absence of oral and pharyngeal residue were evaluated. Regarding oral phase, lip closure, lingual elevation and tongue movement to palatal seal were preserved in both bulbar symptoms-negative and bulbar symptoms-positive patients. Both components of bolus preparation/mastication, and initiation of pharyngeal swallow were preserved in bulbar symptoms-negative patients, but impaired in bulbar symptoms-positive patients. The components of bolus transport and oral residue were affected regardless the presence of bulbar symptoms. In the pharyngeal phase of swallowing, it was shown that soft palate elevation and retraction, laryngeal elevation, anterior hyoid excursion, laryngeal closure, pharyngo-esophageal segment opening, tongue base retraction and epiglottic inversion were preserved in bulbar symptoms-negative patients. When the patients presented bulbar symptoms, laryngeal elevation, anterior hyoid excursion and tongue base retraction were impaired. Pharyngeal residue was affected in all patients.

Video ﬂ uoromanometric studies (VFM) have observed that the decrease in the swallowing pressure ﬁ rst appears in the oropharynx [90] . In 40 ALS patients with dysphagia videoﬂ uoroscopic dysfunctions of the oral phase of swallowing, pharyngeal initiation, pharyngeal transport and manometric data revealed low tongue driving forces and pharyngeal contraction amplitudes but normal relaxation of the upper esophageal sphincter [89] . Other VFM study in 10 ALS patients with no symptoms of dysphagia and a normal VFS observed an increase in the pharyngeal contraction time and in residual pressure after relaxation of the upper esophageal sphincter [89] .

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In summary, frequent VFS signs in patients with ALS are delayed bolus transport from oral cavity to pharynx and decreased pharynx contraction. Video ﬂ uoroscopy can reveal alteration in the swallowing process in asymptomatic ALS patients. See supplementary material for Clinical Question 7 .

3.8. Clinical Question 8: What are the therapeutic effects of behavioral, rheological and rehabilitation treatments for OD in patients with ALS?

Recommendation 11:

In ALS patients with muscular fatigue and long lasting meals, patients should be advised to fractionate and enrich their meals with energy or de ﬁ cient nutrients. If weight loss progresses, oral nutritional supplementation should be recommended.

Grade of recommendation: GPP e strong consensus $\mathbf{\{95\%}}$ agreement)

Recommendation 12:

In ALS patients with moderate dysphagia, dietetic counseling should be advised to adapt the texture of solid and liquids to facilitate swallowing and avoid aspiration. Instrumental study of swallowing function (VFS, FEES or VFS-manometry), if available, can guide the security and ef ﬁ cacy of the texture-modi ﬁ ed diet.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Recommendation 13:

In ALS patients with moderate dysphagia, postural maneuvers (such as chin-tuck posture) should be recommended to protect the airway during swallowing.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

There is no strong evidence in the literature for dysphagia intervention (compensatory and rehabilitative practices) in patients with ALS, probably due to the dif ﬁ culty in the design of RCT in this devastating disease. Furthermore, some compensation techniques described in the literature for the treatment of dysphagia cannot be directly used in ALS patients due to the physiopathology of dysphagia and the special relevance on muscle atrophy and fatigue.

Patients who experience appreciable levels of fatigue should be advised to eat their food as several small meals a day. Dietetic counseling should focus on meal enrichment by use of high-calorie foods. In case of constipation caused by abdominal weakness, dietary ﬁ ber can be added to the diet. The triggering of the swallowing re ﬂ ex can be enhanced by emphasizing taste or temperature.

Adapting bolus characteristics: The initial management of dysphagia is based on dietary counseling, and modi ﬁ cation of food texture (soft, semisolid or semiliquid states) is often required to compensate for a poor oral preparation phase and ease oral and pharyngeal transport while avoiding episodes of choking [57,96,97] . In patients whose swallowing is delayed, the use of thicker liquids, semisolid foods with a high water content, such as jelli ﬁ ed water are suggested as better alternatives to thinner liquids and can help alleviate aspiration. However, there is not suf ﬁ cient evidence in the literature to assess the ef ﬁ cacy of the modi ﬁ ed-consistency food and liquids in the treatment of dysphagia in ALS patients.

Postural maneuver: Solazzo [81] assessed the effect of different postural maneuvers in 81 ALS patients with dysphagia evaluated with video ﬂ uoromanometry: chin-down, or chin-tuck posture,

head-rotation posture and hyperextended head posture. The results of the study showed that swallowing disorders in patients with ALS differ according to the mechanism involved in relation to disease features and progression. Of the three postural maneuvers, the chin-tuck posture proved to be useful in the majority of cases, given that it offers a valuable protection mechanism for the airways by opening the valleculae and preventing penetration into the larynx. Head rotation is indicated in the case of hypertonicity, incomplete release or premature UES closure, and hyperextended head posture is indicated in the absence of lingual pump only if safe transit is ensured. Lastly, in the frequent case of penetration without aspiration into the laryngeal inlet ( $.23\%$ of patients), throat clearing every three to four swallowing acts can prevent possible postswallowing inhalation. Goeleven [89] evaluated 40 patients with VFM, and found that both the oral as well as the pharyngeal stage of swallowing may be compromised in the majority of ALS patients $(97\%)$ , and aspiration, even without clinical aspiration signs or subjective complaints, can be present in $22\%$ of patients. No speci ﬁ c postural maneuvers were suggested in this article.

Other therapies: Saliva problems have been studied with respect to their possible relation with dysphagia management. Both volume and saliva have been proposed as factors that can negatively affect swallowing in ALS patients. Recently, the National Institute for Health and Care Excellence (NICE) [98] has addressed the saliva problems for nutrition management in people with motor neuron disease (MND) and found only indirect evidence from other study populations to recommend pharmacological treatments as antimuscarinic therapy or botulinum toxin A to manage sialorrhoea. No evidence has been found to link the treatment of saliva problems with the improvement of dysphagia. See supplementary data for Clinical Question 8 .

3.9. Clinical Question 9: Do early oral protein-energy supplements improve survival in ALS patients?

Recommendation 14:

Nutritional supplementation is recommended for ALS patients who do not cover their nutritional requirements with an enriched diet. However, there is insuf ﬁ cient data to af ﬁ rm that oral nutritional supplementation can improve survival in ALS patients.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Few interventional studies with control group exist and focused on this subject. The study of Dorst et al. in 2013 compared the impact of two oral nutritional supplements (ONS) high caloric/high fat versus high caloric/high carbohydrate taken during the disease $(3\times200\;\mathrm{ml},$ , 150 kcal per 100 ml. ONS with high fat contained $35\%$ fat, $50\%$ carbohydrate, and $15\%$ protein, high carbohydrate contained ONS with $0\%$ fat, $89\%$ carbohydrate, and $11\%$ protein) [56] . No survival analysis was performed during this study. A caloric supplementation with carbohydrates seems bene ﬁ cial on survival. Indeed, a recent study of Wills et al. in 2014 found better survival in patients taking this supplementation $(1.5\,\mathrm{kcal/ml}$ of which $29.4\%$ calories are from fat) administered with feeding tube during the disease compared to controls having an isocaloric diet during 5 months of follow-up $\mathbf{\tau}(\mathfrak{p}=0.01)$ ) [99] . There was no signi ﬁ cant difference between the control group and patients taking high caloric/high fat supplementation ( $^{,}1.5~\mathrm{kcal/mol}$ of which $55\%$ calories are from fat). Two interventional double blind studies with control group are in the process of inclusion of patients. The ﬁ rst carried out in France,

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consists to give at diagnosis 1, 2 or 3 high caloric/high protein oral nutritional supplements (300 kcal/unit and $_{18\mathrm{~g~}}$ of protein/unit or 322 kcal/unit and $18.6~\mathrm{g}$ of protein/unit) versus group control. The second carried out in Germany consists to give high caloric/high fat ONS $(4.5\mathrm{~kcal/m}$ , $100\%$ lipids) 405 kcal/90 ml/day versus placebo 8 kcal/90 ml/day [100] In summary, there are few data available in the literature to clearly answer this question. Some ongoing studies can help to answer in a most appropriate form this clinical question. See supplementary data for Clinical Question 9 .

3.10. Clinical Question 10: Does enteral nutrition (EN) improve quality of life in ALS patients?

Recommendation 15:

EN may positively affect some aspects of quality of life. Since the impact of EN on quality of life of ALS patients is dif ﬁ cult to estimate and has not been adequately addressed in available studies, we recommend that the pros and cons of EN are adequately discussed with the patient, family and caregivers when EN is proposed.

Grade of recommendation: 0 e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

Much can be done to alleviate the large variety of symptoms that ALS patients suffer [98] , also as a consequence of swallowing impairment. As a result of dysphagia, food and ﬂ uid intakes are gradually decreased because of the fear of coughing and choking and because the time required for eating becomes unsustainably long [35,96] . In addition, an EN access route is useful to ensure suf ﬁ cient ﬂ uid intake and administration of medication.

Although there is consensus that EN represents the medical nutrition therapy modality of choice in ALS patients in whom nutritional needscannot bemet with oral feeding [96] , qualityof life issues such as the loss of the hedonic component of feeding, appetite, thirst, psychological discomfort for the medicalization of feeding should be considered anddiscussed whenproposingEN [98] . The bene ﬁ ts of EN through a PEG appear to be critically dependent on the interval occurring from the diagnosis of ALS to PEG placement and, of course, by the clinical presentation and the consequent evolution of the disease. Only two controlled studies have evaluated changes in quality of life after EN. Neither of these showed clear evidence for improved quality of life after PEG. Mazzini et al. [72] related impressions from patients that their quality of life improved after PEG but reported no concrete data. Mitsumoto et al. [101] reported quantitative results, based on percent of patients who responded af ﬁ rmatively or negatively to speci ﬁ c questions about quality of life after PEG. The majority of the patients $(79\%)$ reported that stabilized nutritional and hydrational status was the most positive effectof PEG. A minority of PEG patients $(17\%)$ reported improved psychological wellbeing with regard to nutrition and $28\%$ listed less fatigue or less time spent on meals and medications [101] . A Cochrane review from Katzberg et al. concluded that quality of life issues have not been adequately addressed in studies and it needs more attention [102] . See supplementary data for Clinical Question 10 .

3.11. Clinical Question 11: Does EN improve survival in ALS patients?

Recommendation 16:

Survival bene ﬁ ts of EN in ALS patients depend on disease presentation and rate of disease progression. We recommend to

consider EN in all ALS patients in whom nutritional needs cannot be met by oral feeding and in whom it is estimated that malnutrition/dehydration could be responsible of reduced survival.

Grade of recommendations: B e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Nutrition is of great concern in ALS as weight loss, malnutrition and dehydration may aggravate muscle weakness, contribute to respiratory weakness, and affect survival [102] . Weight loss is a sign of poor prognosis, and the maintenance of a patient's weight may prolong survival. It has to be highlighted that ALS are diseases which change rapidly and as such it is important to assess hydration, feeding ability, swallowing and nutritional factors, including intake, at every possible opportunity to prevent weight loss [98] . Morassutti et al. documented that if ALS patients are treated before any signi ﬁ cant weight loss occurs, the early nutritional intervention allows good nutritional status to be maintained for a longer period and reduces mortality rate [103] . With inevitable disease progression, dysphagia and swallowing complications signi ﬁ cantly contribute to reduced survival [104] .

The importance of nutritional management is being increasingly recognized but the evidence for a survival advantage after EN is con ﬂ icting [26] . Recently, Chhetri et al. did not ﬁ nd a survival advantage with EN except for those patients who received it more than 500 days after symptoms onset, suggesting that the early requirement for EN may indicate an aggressive illness and therefore a less favorable prognosis [105] . A Cochrane systematic review [102] showed the results of 11 controlled studies comparing PEG feeding to oral feeding. All of these 11 studies tested for a possible survival advantage. Moreover, in patients who underwent PEG placement early in their disease course, survival increased likely owing to the improvement of their nutritional status [106,107] . The lack of a survival advantage should however not dissuade clinicians from recommending enteral feeding to patients with dysphagia and/or malnutrition. See supplementary data for Clinical Question 11 .

3.12. Clinical Question 12: What is the best timing for gastrostomy tube in ALS patients? Is there a relationship between survival and respiratory function at the time of gastrostomy?

Recommendation 17:

Gastrostomy should be discussed at an early stage, and at regular intervals as ALS progresses, according to the evolution of the swallowing problems of safety and ef ﬁ cacy. The detection of dysphagia, long duration of meals, weight loss, poor respiratory function, risk of choking and wishes of the patients should guide the decision to place the gastrostomy.

We recommend to perform the gastrostomy before severe weight loss occurs and before respiratory function is severely impaired.

Degree of recommendation: GPP- strong consensus (100% agreement)

Recommendation 18:

The decision to place a gastrostomy should be made in collaboration with the patient following discussion of his/her wishes and the risks and bene ﬁ ts of the procedure.

Degree of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

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Recommendation 19:

The bene ﬁ ts of early placement of a gastrostomy should be explained, as well as the possible risks of a late gastrostomy (low critical body mass, respiratory complications, different methods of insertion, and a higher risk of mortality and procedural complications due to low weight).

Degree of recommendation: GPP e strong consensus ( $\mathbf{\lambda}\mathbf{95\%}$ agreement)

Commentary:

Gastrostomy feeding is recommended to provide long-term enteral nutrition therapy for patients with ALS with severe dysphagia [55] . However, current practice in relation to timing of gastrostomy insertion is not clear and is based on consensus and expert opinion. Recently, the NICE [98] has addressed the question about the appropriate timing of placement of a gastrostomy tube for nutrition management in people with MND. No RCT or relevant high quality studies were identi ﬁ ed to answer this question, and they stated several recommendations based on informal expert consensus. Gastrostomy could be bene ﬁ cial for the survival, quality of life, and nutritional outcome of patients with ALS, but there is a lack of high-quality evidence relating to these aspects of the intervention because of ethical reasons to perform a randomized control trial. For this reason, the best evidence should be acquired through prospective cohort studies comparing patients undergoing gastrostomy with those who refuse the procedure, or from large retrospective studies focusing on patients underwent gastrostomy.

McDermott et al. [108] , in a large, longitudinal, prospective study (ProGas) explored the 30-day mortality after gastrostomy placement in a multicenter study including 330 ALS non-ventilated patients, and as secondary outcomes they analyzed complications of the gastrostomy insertion procedure, median survival time from gastrostomy placement, nutritional status change and selfperceived quality of life changes after gastrostomy. In this study, the regression model to assess mortality risk included variables as weight loss at the time of gastrostomy compared with weight at diagnosis ( ${\it\Delta\phi}_{\mathrm{{\Lambda}}<10\%}$ weight loss and ${>}10\%$ weight loss subgroups), forced vital capacity at the time of gastrostomy insertion, age at the onset of amyotrophic lateral sclerosis, site of amyotrophic lateral sclerosis symptom onset (bulbar and limb subgroups), and ALSFRSR monthly decline rate. Prognostic factors for mortality at 30 days were signi ﬁ cantly related with age of onset of ALS (HR 1.035 [95% CI 1.008 e 1.063]; ${\mathsf p}=0.011$ ) and weight loss before gastrostomy $(>\!10\%$ weight loss subgroup compared with the ${<}10\%$ weight loss subgroup, HR 2.514 [1.490 e 4.243]; ${\tt p}=0.001$ ). Gastrostomy feeding prevented weight loss in half of the patients, and led to weight gain in $25\%$ of them. The nutritional data suggested that the greater the percentage of weight loss at the time of gastrostomy from diagnosis, the less likely the patients recovered this loss after gastrostomy. These results suggest that patients might bene ﬁ t from early gastrostomy, i.e. before substantial weight loss that might not be reversible has occurred. Dorst et al. [109] , in a multicenter trial, explored the outcome of 89 ALS patients submitted for PEG in a 3 years follow-up study. The overall survival from time of PEG insertion was $18.9\pm1.6$ months, independent of BMI, ALSFRS-r, and FVC. Patients with less overall weight loss (less than $5\ \mathrm{kg}.$ ) and higher cholesterol levels $(>\!220\,\mathrm{mg/dl})$ at time of PEG insertion had a better survival $(21.5\pm2.1$ vs $15.3\pm2.4$ months, $\mathsf{p}=0.025,$ ).

The relation between respiratory function and risk of mortality and outcome after gastrostomy has been a matter of controversial. Chi o, in 2004 [110] , alert about signi ﬁ cant decreased survival in ALS patients with moderate to severe respiratory impairment underwent PEG, in comparison to those in which radiologically guided

gastrostomy was performed. While the American Academy of Neurology [55] and EFNS Task Force [57] recommend to perform the gastrostomy with a forced vital capacity of ${>}50\%$ of predicted values, several studies demonstrate that gastrostomy could be performed with security in patients with worse respiratory function [111] . Pena [112] conducted a study with 151 ALS patients and analyzed the predictors for mortality after the gastrostomy placement. Of note, patients with FVC ${<}50\%$ at the time of gastrostomy were all on non-invasive ventilation and gastrostomy procedure was performed with ventilator support in patients with respiratory symptoms, low FVC or abnormal oximetry. Only age at diagnosis of ALS was identi ﬁ ed as an independent prognostic factor for survival in this study, although patients with lower FVC $(<\!50\%)$ have higher ﬁ rst-month mortality. Spataro [113] analyzed the survival of 76 ALS patients with dysphagia hat accepted PEG, and they compared the outcome with 74 ALS patients with dysphagia that refused the procedure. Among bulbar-onset patients, PEG users showed a median survival time longer than those with no PEG (28 months vs. 25 months), even though the difference was not signi ﬁ cant. Conversely, spinal-onset patients with dysphagia and PEG lived signi ﬁ cantly longer than those who refused PEG (44 months vs. 36 months, $\mathsf{p}=0.046\$ ). Survival in patients with PEG was not affected by the severity of the respiratory impairment, as measured by forced vital capacity. In the study of Dorst [109] , patients with a very compromised respiratory status were included (35 patients with $\mathsf{F V C}<50\%$ of predicted values), and survival was not different of patients with $\mathsf{F V C}>50\%$ (40 patients). There are no studies focusing on ALS patients with FVC below $30\%$ of predicted values, but individual cases are included in some series [113] . The American Academy of Neurology [55] recommends to refuse gastrostomy when FVC was lower than $30\%$ , and to consider other forms of palliative care. As a criticism for recommend or refuse gastrostomy depending on FVC, we should consider that ALS patients with dysphagia, in particular those with a primary bulbar involvement, may perform poorly on spirometry because weakness of the orofacial muscles. See supplementary data for Clinical Question 12 .

3.13. Clinical Question 13: What is the best approach for gastrostomy in ALS patients: percutaneous endoscopic gastrostomy or radiologic gastrostomy?

Recommendation 20:

We recommend PEG as the preferred approach for gastrostomy. When available, in more frail patients, RIG positioning by expert team may be indicated. PEG-J or PEJ may be considered in selected patients.

Grade of recommendation: 0 e strong consensus (97% agreement)

Commentary:

PEG is the most appropriate and commonly used enteral access for medium- and long-term EN. A viable alternative to PEG is represented by radiologically inserted gastrostomy (RIG). The greatest advantage of RIG is placement safety even in patients with significant respiratory impairment [114] . The disadvantages of RIG are the risk of obstruction, because of its small (narrow) diameter, and dislocation of the tube. Thornton et al. compared the effectiveness of RIG to PEG and, despite a greater technical success with RIG, they did not ﬁ nd differences in complications or survival rates between the two techniques [115] .

The ProGas study documented that patients who underwent radiologically inserted gastrostomy had a signi ﬁ cantly increased rate of gastrostomy tube-related complications because narrow in

diameter and not securely ﬁ xed as those inserted by PEG [108] . In contrast, Allen et al. performed a retrospective study on gastrostomy tube placement methodology and found that RIG was more often successful and less often associated with aspiration with respect to PEG [116] . The ProGas study indicates that overall mortality after gastrostomy insertion is independent of the gastrostomy method and is driven by the patient age at the onset of amyotrophic lateral sclerosis and the percentage of weight loss from diagnosis to the time point of gastrostomy [108] .

Decision-making criteria that in ﬂ uence the selection of method of gastrostomy are: status of the respiratory function of the patient; clinical condition of the patient; anatomical issues contraindicating the use of a speci ﬁ c method; availability of service and patient management following gastrostomy [117] . Gastrostomy should be discussed at an early stage, as ALS-MND progresses, and it should take place without unnecessary delay. PEG remains the preferred method for gastrostomy for patients with good respiratory function (forced vital capacity ${>}50\%.$ ) and overall good clinical condition, whereas RIG is preferred, when available, for more frail patients with moderate or severe impairment of the respiratory function [117] . See supplementary data for Clinical Question 13 .

3.14. Clinical Question 14: Is parenteral nutrition (PN) indicated in ALS?

Recommendation 21:

EN (tube feeding) should be preferred over PN in ALS patients who need nutritional therapy.

In the acute setting, PN can be used if EN is contraindicated or non-feasible.

Home PN is generally not indicated in ALS patients. In case of patient ’ refusal or non-feasibility of EN, risk-to bene ﬁ t ratio, ﬁ nancial burden and ethical issues should be evaluated before considering Home PN.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

Most reviews and clinical guidelines recommend the use of EN over PN in ALS patients who require medical nutrition therapy, as in other clinical situations [57,61,98] . In the acute setting and during a short-term period, PN can be indicated in ALS patients if EN is contraindicated or non-feasible (e.g. gastrointestinal hemorrhage, ileus, gastrostomy placement failure, etc.). Only a few studies have been published to assess the feasibility and complications of home PN in ALS patients. None of them have compared PN with other procedures (such as PEG or RIG) in a prospective way.

Verschueren et al. undertook a single center study in 30 ALS patients with advanced ALS, who were treated with HPN because of respiratory insuf ﬁ ciency and EN was refused or impossible [118] . The results were compared with those obtained retrospectively on a group of 35 patients who underwent PEG, who were subdivided into patients with respiratory insuf ﬁ ciency $(\boldsymbol{\mathrm{n}\ =\ 9})$ ) and those without respiratory insuf ﬁ ciency $\mathbf{\check{n}}=26\mathbf{\check{n}}$ ). PN was administered through a central venous catheter. Twenty patients received this treatment at home. Weight stabilization was achieved in most patients. Mean survival time was $3.5\,\pm\,2.4$ months. Twenty four patients died from respiratory failure, one patient from acute subdural hematoma. Death was due to a catheter related bloodstream infection in one patient and this cause was also suspected in another one. In patients with PEG and respiratory insuf ﬁ ciency, post-procedure survival was similar to that of patients on PN, and signi ﬁ cantly lower than survival in patients without respiratory

insuf ﬁ ciency. Quality of life of patients or caregivers was not speci ﬁ cally assessed in this study.

A French national survey has evaluated the safety of home PN in patients with ALS in a retrospective multicenter study [119] . Data from seventy-three patients, with a mean follow-up of $163\pm197$ days (11,908 catheter days) are described. Most patients were in advanced stage of their disease (mean disease duration $35\,\pm\,37$ months, mean FVC $39.6\,\pm\,18\%)$ Home PN was chosen because of severe respiratory failure $(69\%)$ , gastrostomy refusal ( $.22\%$ , dementia $(6\%)$ or gastrostomy placement failure. The median survival after PN was $2.8\,\pm\,1.12$ months. Total central venous catheter complication rate was 3.11 per 1000 catheter days (1.93 septic and 1.09 mechanical complications). Death was due to septic shock in eight patients. Metabolic complications were frequent (2.62/1000 catheter days), but without serious consequences. See supplementary data for Clinical Question 14 .

3.15. Clinical Question 15: Does physical activity improve survival in ALS patients?

Recommendation 22:

There is little evidence concerning the impact of physical activity once ALS has been diagnosed. Some evidence suggests that endurance as well as resistance exercises can slow the progression of the disease and may improve functionality as well as QoL. Thus, physical activity should be advised as long as it does not worsen the physical state of the patient.

Degree of recommendation: 0 e strong consensus (100% agreement)

Commentary:

A systematic literature review performed between 2002 and 2006 reported that physical activity is probably not a risk factor of developing ALS [120] . More recently, an observational study on 636 sporadic ALS patients and 2166 controls found a higher risk of ALS with higher leisure time physical activity (sports, hobbies). However, the authors could not ﬁ nd an association with the level of occupational physical activity nor a dose e response relationship between physical activity and ALS. They concluded that ALS may rather be promoted by a genetic pro ﬁ le or lifestyle mode related to physical ﬁ tness [121] . Another study included over $800^{\prime}000$ men born in Sweden, followed over 20 years. Eighty- ﬁ ve patients died from ALS. The authors found an association between cardiovascular ﬁ tness, measured or estimated, at baseline and death at an early age [122] . Thus, there are still con ﬂ icting results regarding the impact of physical activity prior to ALS diagnosis.

Few evidence exist concerning the impact of physical activity once ALS has been diagnosed. However, the studies published on that topic show that endurance as well as resistance exercises slow the progression of the disease and may improve quality of life [123] . See supplementary data for Clinical Question 15 .

4. Parkinson's disease

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder resulting from dopamine depletion in the brain. The main symptoms include tremor, muscular rigidity, bradykinesia and postural instability. As PD progresses, a variety of other symptoms emerge, including dysphagia, dysarthria impaired gastrointestinal motility and gastroparesis, fatigue, depression and cognitive impairment. Drug therapy is essential to control symptoms and to maintain mobility in PD, and acts by replacing or mimicking dopamine in the brain.

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Patients with PD are at increased risk of malnutrition and weight loss, and nutritional status should be monitored routinely regularly throughout the natural history of the disease [124] . Malnutrition in PD patients is probably under-reported, and can be found in about $15\%$ in community-dwelling patients with PD and other $24\%$ patients are at medium or high risk of malnutrition [125] . Several predictors of malnutrition have been found: older age at diagnosis, higher levodopa equivalent daily dose/body weight, anxiety and depression and living alone.

Dysphagia in PD usually occurs in the advanced phases of the disease, although sometimes it is present at onset. Functional alterations in oropharyngeal and esophageal motility can be present in about $60{-}80\%$ of patients, but must be asymptomatic. Gastrointestinal dysmotility has potential implications for enteral feeding strategies.

4.1. Clinical Question 16: Do patients with Parkinson's disease (PD) have higher nutritional requirements?

Recommendation 23:

We recommend that PD patients should undergo regular monitoring of nutritional and vitamin status during the course of the disease. Particularly, attention should be focused on changes in body weight, and the need of supplementing vitamin D, folic acid and vitamin B12.

Grade of recommendation B e strong consensus (91% agreement)

Commentary:

PD patients experience several changes in body weight during the course of the disease [124,126,127] . Weight loss and gain may both occur. Causes of weight changes are not clear yet and different mechanisms have been invoked in determining them, particularly changes in energy expenditure and eating behavior [124,126 e 128] . Indeed, weight loss is a key feature of PD and a meta-analysis [129] has con ﬁ rmed that PD patients have a signi ﬁ cantly lower BMI than healthy controls. Weight loss may be present at diagnosis and it has been associated with disease progression [124,126 e 129] . In this process, a major role is likely played by the increase in energy expenditure associated with the onset and/or worsening of dyskinesias and rigidity [124,126,127] which is not fully compensated by an increase in energy intake [124] occurring with disease progression. Nonetheless, the impact of gastrointestinal dysfunction e namely dysphagia, sialorrhea and constipation e on energy balance should be always taken into account although the exact role still needs to be clari ﬁ ed [128,130,131] . Conversely, while body weight gain in the initial stages of the disease is likely dependent on dopaminergic treatment, which improves motor symptoms and could modulate eating behavior [128,131,132] , in the advanced stages of the disease it is almost uniquely secondary to neurosurgical procedures [137] . Deep brain stimulation (DBS) is responsible for weight gain in the majority of patients due to reduction in energy expenditure e associated also with the reduction of motor complications (dyskinesias) e and changes in eating behavior [128,131,132,137] . The importance of weight management is multifaceted. Although weight loss primarily involves fat mass in patients with PD, with substantial sparing of skeletal muscle mass and low risk of sarcopenia [124,134,135] , malnutrition has been associated with disease severity [126,127] . Besides, it is associated with an increase in the daily dose of levodopa (both total and per kilogram of body weight) which could induce or worsen dyskinesias. However, the prognostic role of weight loss in PD has to be determined. On the other hand, patients undergoing DBS should be

actively monitored as weight gain is mainly of fat mass, signi ﬁ - cantly accumulating in the abdominal region [133] . While overweight in PD patients is not usually associated with cardiometabolic complications [134] , DBS induces metabolic disorders increasing the risk of metabolic syndrome [133] . Therefore, regular monitoring of body weight is recommended. Nutritional assessment should be conducted at least on a yearly basis and whenever the clinical conditions change.

PD patients should also undergo active monitoring of vitamin status. Low vitamin D levels have been associated with the risk of developing PD and serum levels are lower in PD patients than healthy controls [136,137] . A large case control-study has shown that, despite of higher food intake, the intake of vitamin D in PD patients is signi ﬁ cantly lower than recommended dietary allowances [138] . Supplementation should be always considered as it seems to slow disease progression e at least in patients with highrisk genotype of the vitamin D receptor [139] . PD patients present also lower bone-mineral density (BMD) e which may further increase the risk of fractures associated with disease-related disability e than age-matched controls [140] . The only RCT available has shown that provision of active form of vitamin D can reduce the risk of fractures in osteoporotic old PD patients by slowing the loss of bone mineral mass [141] . A reduction of homocysteine levels could also contribute to the improvement of BMD [142] . PD patients treated with levodopa show an elevation of homocysteine [143] . This is greater in patients on higher doses of levodopa and is due to levodopa methylation by catechol-O-methyltransferase (COMT) [144] . Accordingly, the concomitant use of COMT inhibitors (e.g. entacapone) may limit the raising of plasma levels, although the regulation is closely linked to vitamin B12 and folate status [143,144] . Interestingly, studies have shown that levodopa-treated PD patients have also lower circulating levels of folate and vitamin B12 [145,146] . On the other hand, administration of these vitamins is effective in reducing homocysteine levels [143,147,148] and should be always considered to prevent neuropathy [149,150] and other complications associated with hyper-homocysteinemia.

There has been growing interest in the role of oxidative stress in the neurodegenerative process. However, data on the association between antioxidantvitamins such as vitamin C, E, A andcarotenoids are still inconclusive [151,152] . PD patients appear also to be characterized by reduced levels of coenzyme Q10 [153] . However, large randomized trials have shown that supplementation with either vitamin E or coenzyme Q10 showed no evidence of clinical bene ﬁ t [154 e 156] . Therefore, the supplementation of these vitamins is not recommended. See supplementary data for Clinical Question 16 .

4.2. Clinical Question 17: When and how should patients with PD be screened for dysphagia?

Recommendation 24:

All patients with Parkinson's disease with a Hoehn & Yahr stage above II or weight loss, low BMI, drooling, dementia or signs of dysphagia should be screened for dysphagia during an ON-phase.

Grade of recommendation B e strong consensus (95% agreement)

Recommendation 25:

A Parkinson's disease speci ﬁ c questionnaire or a water swallow test with the measurement of the average volume per swallow is recommended.

Grade of recommendation B e strong consensus (91% agreement)

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Commentary:

More than $80\%$ of patients with PD develop dysphagia during the course of the disease [157,158] . Sometimes swallowing problems arise even early during the course of the disease [9] . Statistical risk factors for dysphagia in Parkinson's disease are Hoehn and Yahr stage above III, weight loss, BMI below $20~\mathrm{kg}/\mathrm{m}^{2}$ , drooling or sialorrhea and dementia [157,159,160] . Although dysphagia is already reported in patients with a Hoehn & Yahr stage II, this does not seem to be clinically relevant in the sense of risk of aspiration and malnutrition. That is why it is recommended to start a regular screening from stage III on. However, if there are signs of dysphagia, such as coughing during meals or after drinking, pneumonia or subjective dysphagia, a screening and if necessary assessment should be performed irrespective of the stage of the disease.

A meta-analysis showed that the prevalence of oropharyngeal dysphagia based on subjective outcomes in PD patients is $35\%$ and increases to $82\%$ by taking objective measures of swallowing dysfunction into account [161] . This impressively demonstrates that in most PD patients oropharyngeal dysphagia is without obvious symptoms. Only $20{-}40\%$ of PD patients are aware of their swallowing dysfunction, and less than $10\%$ of PD patients report spontaneously about dysphagia [162,163] . In addition, silent aspiration is very common in PD [162 e 165] . This explains why it is necessary to actively screen PD patients for dysphagia. Dysphagia is associated with a high risk for decreased intake of food and ﬂ uids, aspiration and pneumonia [166] . Pneumonia is the most frequent cause of death in Parkinson's disease and suspected to be substantially related to dysphagia [167] . Fear of aspiration and choking, food-modi ﬁ cation and being dependent on others for food intake may alter also social and psychological wellbeing of patients with PD [168] .

Even without obvious symptoms, dysphagia is clinically relevant and should be detected, i.e. should be screened for. A ﬁ rst step of screening can be a self-report questionnaire. Two standardized PDspeci ﬁ c questionnaires have been published for this purpose: the swallowing disturbance questionnaire (SDQ) and the Munich Dysphagia test-Parkinson's disease (MDT-PD). With these questionnaires, PD-related dysphagia is identi ﬁ ed with a sensitivity of $81\%$ for both questionnaires, and a speci ﬁ city of 82 and $71\%$ , respectively [169,170] . The SDQ is more simple and easier to apply. The MDT-PD is able to detect milder forms of oropharyngeal dysphagia. An alternative or next step should be the application of a swallow-screening test. The usual water swallowing test as used in acute stroke patients has been shown to be non-predictive of severe oropharyngeal dysphagia in PD patients [159] . Although not yet suf ﬁ ciently validated, experts recommend estimating the maximum swallowing volume as a screening test [171 e 173] . It uses a gradual increase of the volume of water that has to be swallowed. PD patients with a maximum swallowing volume below $20\;\mathrm{{ml}}$ are very likely to suffer from dysphagia. However, this test has only been evaluated in small study populations and has not yet been validated against instrumental tools [171 e 174] . A more simple and practical alternative is the measurement of the average volume per swallow [172] . Here, a de ﬁ ned volume of water (i.e. 100 ml) should be drunk in a usual manner and the time needed and the number of swallows is measured. The calculated volume per swallow is signi ﬁ cantly lower in PD patients than in controls (13 vs 21 ml) [172,175,176] . Comparably, the volume that can be swallowed with one swallow is measured with the volume-viscosity swallow test in a stepwise manner (5, 10, 20 ml) for multiple consistencies [79] . This screening test is validated in PD patients against VFS. Thus the claimed $100\%$ sensitivity for aspiration is in contrast with the data given by some studies, which report frequent silent aspiration in PD [159,164,177,178] . See supplementary data for Clinical Question 17 .

4.3. Clinical Question 18: When and how should a clinical or instrumental assessment of dysphagia in PD be performed?

Recommendation 26:

All patients with Parkinson's disease who were screened positive for dysphagia or demonstrate rapid deterioration of the disease, pneumonia or other signs of dysphagia should undergo an instrumental dysphagia assessment.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 27:

The assessment should be done preferably with FEES, and if not available, with VFSS. If instrumental dysphagia assessment is not available, clinical assessment should be performed instead.

Grade of recommendation: GPP e strong consensus (95% agreement)

Commentary:

Clinical assessment of dysphagia in PD patients is challenging and often delivers unreliable results. Silent penetration and aspiration is a frequent ﬁ nding in PD and cannot be reliably detected by clinical assessment [164,165] . In addition, studies investigating the optimal way to perform a clinical swallowing examination in PD patients are lacking [179] .

It has been shown that dopaminergic as well as nondopaminergic mechanisms are involved in the development of dysphagia in PD [157] . Therefore, it is not predictable whether or not dopaminergic treatment will have a bene ﬁ cial effect on dysphagia, which has to be tested where necessary [180] .

FEES and VFS study (VFSS) are both considered gold standard for evaluation of PD-related dysphagia and should be the ﬁ rst choice assessment tool [157,181] . Considering the fact that the reliability of VFS in PD was questioned by one study [182] , FEES entails also several practical advantages in comparison to VFS. It does not involve any radiation, it needs only minimal cooperation of the patients and may be performed as a bedside method [17] . Furthermore, FEES in PD may directly be utilized as a therapeutic measure, if performed in a feedback approach, described as video assisted swallowing therapy (VAST) [183] . In addition, high-resolution manometry is able to detect isolated or combined esophageal dysphagia in PD patients. It may even identify clinically silent swallowing impairment at an early stage of PD [184] . This method is often combined with impedance measurements, impedance manometry, which may increase the validity of the method [184 e 188] .

Other techniques such as acoustical analysis of voice [189 e 191] , acoustical analysis of swallowing or breathing sounds [192 e 194] lack high sensitivity or speci ﬁ city and are not broadly available. The same is true for electromyography, which is of some value in the detection of the motor component of dysphagia in PD [195 e 198] . In addition, dynamic magnetic resonance imaging recently demonstrated some results but was not yet applied to PD patients [199,200] . See supplementary data for Clinical Question 18 .

4.4. Clinical Question 19: Does the pharmacological treatment of PD improve dysphagia?

Recommendation 28:

Optimization of the antiparkinsonian treatment should be advised to ameliorate the motor symptoms that contribute to dysphagia in PD patients.

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Grade of recommendation: B- strong consensus ( $\bf{100\%}$ agreement)

Commentary:

Levodopa and other antiparkinsonian drugs signi ﬁ cantly improve the motor features of PD patients. However, there is little evidence about the effect of levodopa on swallowing function in patients with dysphagia. None randomized controlled trials have been design to explore this question, and only one meta-analysis [201] and one very well conducted systematic review of the literature [202] have been published on this topic.

In 2009, Menezes conducted a meta-analysis of ﬁ ve NRCT studies, assessing ﬁ ve outcome measures: oral transit time for thin ﬂ uids, solids, pharyngeal transit time for thin ﬂ uids and solids and presence of aspiration [201] . They concluded that levodopa intake was not associated with a signi ﬁ cant improvement of swallowing dysfunction in PD patients. Some criticisms are published about this meta-analysis [203] (few studies, open-label, short in duration, small in sample size, not assessment of the effect of long duration levodopa treatment, inclusion of a variety of quality design studies, selection bias, poorly de ﬁ ned outcome parameters and dysphagia assessment tools that only explore one part of swallowing). Other authors as Lim et al. [204] concluded, in a very small study, that ef ﬁ ciency of swallowing can be reduced with levodopa treatment, while security of swallow remains unchanged. However, some authors have found improvements in swallowing function related to levodopa treatment [181,205] , including one prospective study in de novo diagnosed PD patients, comparing 140 PD patients in their ﬁ rst year after dopaminergic treatment with 31 patients with no dopaminergic treatment [206] . The improvement in dysphagia probably is mediated through the improvement of motor symptoms (oral preparatory phase time, buccolinguofacial motor score, bradykinesia and rigidity of the tongue, and mandibular movement). Furthermore, the improvement of motor symptoms makes possible the adoption of compensatory postures that increase the airway protection during swallowing. Disease severity (based on the Hoehn and Yahr scale), on/off phase in which treatment was performed, and dysphagia assessment tool can be confounders to take into account in the design of such studies. See supplementary data for Clinical Question 19 .

4.5. Clinical Question 20: Do side effects of drugs used to treat PD in ﬂ uence nutritional status?

Recommendation 29:

Side effects of drugs prescribed for PD might in ﬂ uence nutritional status. We recommend to monitor side-effects and nutritional status and to intervene on an individually tailored basis. For levodopa, speci ﬁ c attention should be given to homocysteine levels and vitamin B status.

Grades of recommendation: GPP e strong consensus (95% agreement)

Commentary:

There are several side-effects related to drugs prescribed for PD that might in ﬂ uence intake and nutritional status, including nausea, vomiting, abdominal pain, dyspepsia, constipation, weight decrease, dry mouth, diarrhea, anorexia and GI disorders [207 e 209] . These side-effects have been mentioned by patients to attribute to their weight loss, as well as changes in taste and smell of food [210] . Hence, in addition to the motor and non-motor

symptoms of Parkinson's disease itself, some available treatments also contribute considerably to the changes in nutritional status [124] . The mechanism of drugs-related weight changes is still not well known and requires further investigation [126] . The use of levodopa may be associated with impaired nutritional status and risk for malnutrition. Increasing doses of levodopa and levodopa equivalent doses have also been found to be related to increased risk for malnutrition, as assessed with the Mini-nutritional Assessment (MNA). These associations were not seen for dopamine agonists [211] . Association between nutritional risk and levodopa has also been shown by others [130] . Research has indicated weight loss among levodopa users, especially in women (which might be due to higher levodopa dose per kg of body weight), and after starting levodopa treatment [212] . In this study, the magnitude of levodopa dose did not seem to be related to weight loss, and was mostly due to reduction in body fat mass [212] . BMI has also been shown to inversely correlate to levodopa treatment, pointing towards dosedependent levodopa associated weight loss [213] . Yet, the true relationship between levodopa use and weight loss needs to be determined as it unknown whether higher levodopa use induce weight loss, or patients with more severe disease receive higher doses of levodopa per kg body weight. Indeed, in more advanced stages, higher doses of levodopa are required to improve the control of worsening motor symptoms. Higher (relative) doses in advanced stages are also associated to dyskinesias which, in turn, have been associated with weight loss [126] .

Levodopa has been found to induce metabolic effects. The literature search included a study on metabolic effects $(\mathsf{n}=10)$ ), showing that levodopa/benserazide $(200\ \mathrm{\meg/}50\ \mathrm{\meg)}$ ) caused metabolic changes in adipose tissue and skeletal muscles disturbing lipid and carbohydrate metabolism. Hence, these results indicate that levodopa/benserazide does not reduce fat wasting through modulation of adipose tissue metabolism. Results pointed towards reduction in muscle glucose uptake, which might induce glucose intolerance [214] . Another small study in seven geriatric Parkinsonian patients showed increased plasma free fatty acids, glucose, growth hormone and cortisol after levodopa administration which were signi ﬁ cantly higher compared to young controls, and only slightly higher compared to aged controls [215] . Longterm treatment with levodopa induces hypersecretion of insulin and growth hormone [124] . Levodopa challenges in PD patients with deep brain stimulation have shown to decrease REE in general, but signi ﬁ cantly increase REE for those patients who had dyskinesias [216] . After the pharmacological change, lipid oxidation remained unchanged but glucose oxidation fell and fasting glycaemia was raised [216] . However, the true interrelationships between those factors need to be established.

Use of levodopa can cause hyperhomocysteinemia [217 e 220] . One study showed dependency upon vitamin B status as assessed by folate, vitamin B12, and vitamin B6. Patients on levodopa seem to have higher requirements for these vitamins to maintain normal homocysteine levels, and supplementation might be warranted [217] . Notably, many patients already take over the counter supplements which might explain the low prevalence of folate or cobalamin de ﬁ ciency [218] . Risk factors for increased homocysteine levels include not solely higher levodopa use but also older age, longer disease duration, and lower serum levels of vitamin B12 and folate [218] . Although the clinical implication of hyperhomocysteinemia in PD patients is not well determined [219] , in general, high homocysteine levels have been linked to cardiovascular diseases, dementia and depression [217 e 219] . In PD patients speci ﬁ cally, a higher relative risk for coronary artery disease has been shown with high plasma homocysteine levels [218] . See supplementary data for Clinical Question 20 .

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

4.6. Clinical Question 21: Are rehabilitation therapies (behavioral, rheological, rehabilitation, neurorehabilitation) effective for the treatment of oropharyngeal dysphagia in PD patients?

Recommendation 30:

Rehabilitation treatment (adapting bolus characteristics, postural maneuvers and exercise programs) should be advised in PD patients with dysphagia in an individual manner, after a multidimensional assessment of the swallowing function. Other techniques such a surface electrical stimulation, repetitive transcranial magnetic stimulation or video-assisted swallowing therapy have not yet enough evidence to make a recommendation.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

There is not strong evidence in the literature for dysphagia intervention (compensatory and rehabilitative practices) in patients with PD. In 2001 a Cochrane systematic review of the literature was performed to examine the non-pharmacological therapies for dysphagia in PD patients [221] . None RCT or other forms of controlled trials were found and the authors concluded that there was insuf ﬁ cient evidence to support or to refuse swallowing therapies in PD. In 2009, Baijens identi ﬁ ed ﬁ ve articles including rehabilitative and compensatory-based studies, identifying positive tendencies in favor of swallowing therapies, although these treatments targeted different aspects of physiology of swallow [222] . Michou et al. [168] reviewed in 2010 the current evidence, and also concluded that clinical practice in this area lacks research evidence. In 2014, van Hooren et al. [223] published a systematic review of the literature searching for effective treatments for dysphagia management in PD patients, including surgical interventions, bolus modi ﬁ cation, neuromuscular electrical stimulation, postural and airway protective maneuvers, and pharmacological interventions, and they found some evidence for expiratory muscle strength training and video-assisted swallowing therapy. However, rehabilitative approach could possibly have greater potential in the long-term to increase swallowing safety and improve quality of life for PD people with dysphagia [224] , although more research is needed to determine the most effective therapy, the duration of the treatment, therapy intensity, timing on therapy start, and the maintenance of improvements.

Adapting bolus characteristics: Adapting bolus characteristics such a consistency or volume can change certain parameters of swallowing safety. Troche et al. [225] compared, in a short trial, the effect of thin versus thickened consistencies on swallowing timing and penetration-aspiration scores in patients with PD. They concluded that pudding-thick liquids resulted in signi ﬁ cantly higher oral transit time and number of tongue pumps than thin liquids, however they found signi ﬁ cantly lower penetrationaspiration scores for pudding-thick liquids, so a safer swallow for people with PD.

Postural maneuvers: Logemann et al. [226] conducted a large study into compensatory approaches for dysphagia management in PD patients, comparing sequentially three strategies commonly used to treat aspiration risk: chin-down posture, nectar-thick ﬂ uids and honey-thick ﬂ uids. The study included 277 patients with PD and 135 with PD and dementia. For all patients group the chindown posture was the least effective at preventing aspiration, and honey-thick liquids were the most effective. Overall, participants had signi ﬁ cantly more episodes of aspiration using the chin-down posture with thin liquids than when taking nectar-thick liquids or

honey-thick liquids. Unfortunately, $39\%$ of patients with PD and $50\%$ of patients with PD and dementia aspirated on all three interventions. Robins et al. [227] explored the ef ﬁ cacy of the mentioned three strategies to prevent aspiration pneumonia in a 3 months follow-up study, and they concluded that neither chindown posture nor thickened ﬂ uids are superior in preventing adverse outcomes of dysphagia in participants with PD or PD plus dementia.

Exercise programs: Exercise program such as expiratory muscle strength training (EMST) have demonstrated improvement in cough and swallow function in PD patients. Individuals that received active EMST for 4 weeks presented with improved penetration/aspiration scores, and improved hypolaringeal complex function (excursion time and displacement) as compared with both their pretreatment assessment [228] and with placebo-controlled group [229] . Argolo et al. [230] , in a short prospective cohort study, evaluated the effect of an oral motor exercise program supervised by a speech language therapist. They performed training with different amounts of thin and thick liquids, puree, and soft solid foods for 5 weeks. The authors found an increase in the strength and range of motion of the mouth, larynx and pharynx, improvement in the oral control of the bolus, coordination between breathing and swallowing and airway protection using a VFS. Diverse structured swallowing programs have been demonstrated their ef ﬁ cacy on improving neuromuscular control of oral phase and tongue function during oral and pharyngeal phases of swallowing, such as intensive Lee Silverman Voice Treatment in a nonRCT of 1 month of duration [231] .

Other interventions : Thermal-tactile stimulation of the anterior faucial pillars has been investigated to improve swallow timing in people with PD. Fifteen PD patients with oropharyngeal dysphagia and pharyngeal swallow delay detected by VFS were submitted for thermal-tactile stimulation [232] , and the technique was effective for reducing pharyngeal transit time and total transit time, but not to reduce oral transit time. Nevertheless, it is not clear that this technique will be associated with a safer and more ef ﬁ cient swallow in PD patients.

Surface electrical stimulation of the submenton region has been used as adjunct to traditional logopedic dysphagia treatment in PD patients. Baijens et al. [233] , in a sequential assignment study with 90 PD patients, explored the effect of motor-level surface electrical stimulation or sensory-level surface electrical stimulation together with logopedic swallowing therapy, and they compared the results with a control group with only traditional logopedic therapy. All the treatments sessions and the examinations were performed during the “ on ” motor phase after the intake of antiparkinsonian medication. After 15 days of treatment, the authors found no statistically differences in VFS or FEES variables between the three treatment groups.

Neuromuscular electrical stimulation of the suprahyoid musculature has been explored combined with traditional logopedic treatment [234] in a RCT including 109 PD patients assigned to three intervention groups in a consecutive manner. The study shows positive effects of dysphagia therapy in patients with PD in all three groups of intervention, but only slight non-signi ﬁ cant differences between groups have been found after one month.

Repetitive transcranial magnetic stimulation, a neurorehabilitation non-invasive technique, has been used to modulate neural activity in targeted focal brain regions. Murdoch et al. [235] showed in a controlled study, that transcranial stimulation in the left tongue area of the motor strip improves the maximum velocity of tongue movements and distance of tongue movements.

VAST is based on a visual cueing mechanism to improve motor and coordination skills in swallowing. Manor et al. [183] evaluated this treatment in 42 PD patients, in a RCT comparing compensatory

and conventional swallowing exercises with or without VAST during 4 weeks. After VAST, the food residue in the pharynx and subjective patient-self-reports about dysphagia signi ﬁ cantly improved compared with conventional therapy alone.

Other treatments as botulinum toxin-A injections have been effective for treating sialorrhoea in PD, but no effects on swallowing has been reported. See supplementary data for Clinical Question 21 .

4.7. Clinical Question 22: Is there a role for protein redistribution and/or low-protein diet in PD patients on levodopa treatment?

Recommendation 31:

In addition to advising PD patient to take levodopa medications at least 30 min before meals, we recommend advising those experiencing motor ﬂ uctuations to try complying with a protein-redistribution dietary regimen to maximize levodopa absorption and ef ﬁ cacy.

Grade of recommendation B e strong consensus $\mathbf{\{90\%}}$ agreement)

Commentary:

Levodopa is the most effective drug in the treatment of PD. Due to its chemical structure it competes with dietary large neutral amino acids for intestinal absorption and transport across the blood e brain barrier. Therefore, all patients are advised to take their levodopa-containing medications about 30 min before meals to avoid interactions [124,236] . However, levodopa-responsive PD patients experiencing motor ﬂ uctuations (sudden/unpredictable changes from phases of optimal motor function or mild dyskinesia [ ‘‘ ON ” state] to phases in which PD motor symptoms reappear [ ‘‘ OFF ” state]) should be recommended to comply with controlledprotein dietary regimens to maximize levodopa absorption and ef ﬁ cacy [236,237] . Redistribution of protein intake throughout the day (low-protein breakfast and lunch and consumption of a secondcourse e with no quantitative restrictions in terms of protein e only at dinner) was found to improve motor function and disability and to increase the duration of “ ON ” state [236] , particularly when the intervention is proposed to patients in the early stages of PD and with onset of PD in younger age. Furthermore, a good-quality randomized, cross-over, single-blind, trial has also shown that the use of low-protein foods designed for patients with chronic renal failure [238] are helpful in achieving protein redistribution. However, patients should undergo active monitoring. This could enable avoiding dropout associated with potential complications including weight loss, micronutrients de ﬁ cits, hunger before dinner and dyskinesias [236,239] . Particularly, patients experiencing the onset or worsening of dyskinesias may require reduction in levodopa doses [236] . One of the objectives of redistribution is to meet daily protein requirements, which could be set to $0.8{-}1.0~\mathrm{g/kg}$ of body weight. Although this advice may appear in contrast with recent recommendations [240] , no adverse effect of protein-redistribution regimens on body composition (e.g. loss of muscle mass) have been reported [238] , at least in the short term. Nevertheless, data on protein redistribution diet in very old PD patients are scant and potential bene ﬁ ts should be balanced along with clinical conditions (e.g. comorbidities, frailty status, etc.) and its feasibility.

The role of strict low-protein diet has not been investigated in good-quality clinical trials and there is no evidence supporting this dietary regimen [236] . Besides, despite recent interest [241] , there is no evidence supporting the use of gluten-free or plant-foodbased diets in PD patient with motor ﬂ uctuations. The dietary management of other gastro-intestinal problems (delayed gastric emptying and constipation) impairing levodopa ef ﬁ cacy may be

also bene ﬁ cial as these can result in reduced bioavailability and higher requirements of levodopa [124,138] .

Similar recommendations can be provided to PD patients treated with continuous duodenal duodopa. Patients should be advised to distribute food intake throughout the day and to divide the protein intake. In case of low-infusion-rate continuous EN by gastric tube feeding we do not give any restrictions but it is advisable to concentrate it during the night hours if possible in order to limit interactions. Finally, in tube-fed patients still treated with oral formulations of levodopa-containing medications we could suggest the interruption of enteral nutrition for at least 1 h before and 30 e 40 min after drug administration. See supplementary data for Clinical Question 22 .

4.8. Clinical Question 23: Does medical nutrition therapy improve quality of life or survival in patients with PD?

Recommendation 32:

We advise that PD patients should receive medical nutrition therapy to improve well-being and quality of life. Medical nutrition therapy should be tailored to individual requirements. Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Quality of life (QoL) is related to nutritional status; research shows that PD patients who are moderately malnourished have lower quality of life than patients who are well nourished [242] and MNA scores are inversely correlated to quality of life domains, especially mobility and emotional well-being domains [243] . There is however very limited literature on the effectiveness of medical nutrition therapy on the improvement of the quality of life or survival of patients with PD. Individualized nutritional information provided by a dietician with weekly telephone contact did not show improvement in quality of life compared to written information only [242] . Two years supplementation of creatine has been shown to have some bene ﬁ cial effects for mood over placebo treatment, but did not in ﬂ uence overall quality of life or disease progression [244] . A review on the use of antioxidants and supplements has shown a limited role for treatment with some bene ﬁ t for CoQ10 supplementation on Uni ﬁ ed Parkinson Disease Rating Scale (UPDRS) activity daily living scores, although this seemed inconsistent among studies [245] . Finally, since food-derived amino acids compete with levodopa for entry into the brain across the blood e brain barrier, protein redistribution diets have been proposed and demonstrated to improve the ef ﬁ cacy of levodopa. Positive effects have been found not only on motor symptoms but also on disability score [236] , both which have been linked to reduced QoL. However, ad-hoc evaluations of QoL in PD patient adhering to protein redistribution diets are not available. The effect of medical nutrition therapy on survival in PD patients has not been studied, which urges the need for intervention trials on this topic. See supplementary data for Clinical Question 23 .

4.9. Clinical Question 24: Do patients with PD who suffer from constipation bene ﬁ t from diet therapy?

Recommendation 33:

PD patients with constipation can bene ﬁ t from the use of fermented milk containing probiotics and prebiotic ﬁ ber in addition to common dietary advices aimed at increasing the intake of water and ﬁ ber.

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Grade of recommendation: B e strong consensus (91% agreement)

Commentary:

Constipation is the most frequent non-motor symptom and manifestation of gastro-intestinal dysfunction in PD patients [124,131,246] . It is mainly the consequence of neurodegenerative process involving the enteric nervous system but it could be also the side effect of certain PD medications (mainly dopamine agonists and anticholinergics) [131] . Furthermore, reduced physical activity associated with motor impairment is considerable contributing factor [124] . Nonetheless, it is worth mentioning that defecatory dysfunction in PD may be due not only to slow colonic transit but also to pelvic ﬂ oor dyssynergia [124,131,246] . Unfortunately, few treatment options either pharmacologic or non-pharmacologic have been tested and investigated in this patient population. Accordingly, the use of the same treatment algorithm for patients with idiopathic chronic constipation is recommended also for PD patients [131] [131,247] . Non pharmacological lifestyle modi ﬁ cations could be proposed to improve colonic transit. Common nutritional management strategies include the increase of ﬁ ber and ﬂ uid intake [124,131,247] . In a small RCT $\mathbf{(n=7.}$ ) with high risk of bias the use psyllium was found to increase the total number of bowel movements but did not improve other parameters of defecation (stool consistency, straining effort, pain on defecation, or completeness of evacuation) [248] . After a positive preliminary experience [249] , a recent large RCT $\mathbf{\dot{n}}=120,$ ) with low risk of bias has demonstrated that, compared to placebo, the daily consumption of a fermented milk containing probiotics and prebiotic ﬁ ber for 4 weeks resulted not only in an increased number of complete bowel movements but also in an improvement of stool consistency, as well as in a larger reduction in the use of laxatives [250] . Despite the fact that the experimental product used in this trial is not available on the market, the use of probiotics as adjuvant treatment for constipation could be extensively recommended to PD patients due to its safety pro ﬁ le. See supplementary data for Clinical Question 24 .

5. Multiple sclerosis

Multiple sclerosis (MS) is a chronic, in ﬂ ammatory and autoimmune disease of the central nervous system, leading to widespread focal degradation of the myelin sheath, variable axonal and neuronal injury, and disability in young adults. From the clinical point of view, there are at least two main forms of the disease: the relapsing-remitting MS (RRMS, concerning about $85\%$ of clinical cases) and the primary-progressive MS (PPMS, affecting about $15\%$ of the clinical cases). In RRMS, the conduction of nerve impulses along the axon of the neuron may be affected during an acute inﬂ ammatory phase (relapse), but tend to improve with healing during the remission phase. Over time, relapses cause extensive damage and scarring of the myelin sheath with progressive loss of neuronal function. Pathogenesis of PPMS is characterized by progressive neurological damages rather than relapses and remissions. The cause of MS is unknown, but research suggests that genetic, immunological and environmental factors, such as a common virus, may all be involved in a complex etiology.

Weight loss, malnutrition and even cachexia are wellrecognized features of patients with MS [251] . The possible causes of weight loss and malnutrition in MS have been well identi ﬁ ed: reduced mobility and fatigue, inappropriate diet, physical dif ﬁ culty for eating or drinking, poor appetite, poor sight, reduced cognition and dysphagia. Medical nutrition therapy should be guided by the identi ﬁ cation of the cause of weight loss and malnutrition in each

case. Dysphagia can be one of the most important complications of MS that could affect nutritional status [252] . Dysphagia in MS usually results from brain stem involvement, and is often accompanied by speech dif ﬁ culties.

5.1. Clinical Question 25: Is there a role for a dietary prevention of MS?

Recommendation 34:

We suggest a diet lower in saturated fat and higher in polyunsaturated fatty acids from food sources for the prevention of MS. Grade of recommendation: B e strong consensus (91% agreement)

Recommendation 35:

We do not recommend supplementation of n-3 fatty acids for the prevention of MS and other demyelinating diseases.

Grade of recommendation: 0 e strong consensus (95% agreement)

Commentary:

Dietary factors have repeatedly been studied as a way to prevent the occurrence of MS, without signi ﬁ cant positive results [253] . The main constituents of the diet that have been studied as a way to prevent the occurrence of MS and other demyelinating diseases are speci ﬁ c dietary patterns, the type of dietary fat, with emphasis on polyunsaturated fatty acids (PUFA) intake, vitamin D, other vitamins, minerals and trace elements and gluten [254] .

Epidemiological studies have suggested an association between the incidence of MS and the intake of saturated fat of animal origin. In 1950 Swank was the ﬁ rst researcher to suggest a positive link between MS and high saturated fat intake [255] . According to his study, the amount of saturated fat consumed during the Second World War was lower in northern countries, i.e. Norway, Denmark, Sweden, Switzerland, Holland, Belgium and England and so was the incidence of MS. In later studies he also noted that countries with higher consumption of polyunsaturated fat intake and lower of saturated fat, such as the coastal areas of Norway had lower incidence of MS [256] .

Polyunsaturated fatty acids intake was of major interest and several pathophysiological pathways were suggested for omega 3 ( u -3 or n-3) and omega-6 ( u -6 or n-6) fatty acids, based on their immunoregulatory, anti-in ﬂ ammatory and anti-coagulant properties as well as the signi ﬁ cant role of these fatty acids on the Central Nervous System (CNS) as compounds of the myelin membrane [256,257] . In a very recent study, higher consumption of n-3 polyunsaturated fatty acids from ﬁ sh origin was associated with lower risk of ﬁ rst clinical diagnosis of MS [258] . However, there is a limited number of studies for the direct effect of polyunsaturated fatty acids supplementation on the risk of developing MS and other demyelinating diseases. In patients with MS there are several trials testing the ef ﬁ cacy of the supplementation of n-3 and n-6 fatty acids on disease activity measured with magnetic resonance imaging, relapse rate and disability progression (see Clinical Question 26). The results of the majority of the studies are either neutral regarding the effect of these fatty acids on the primary outcome parameters [259] , or the quality of the positive studies is low, not allowing extracting safe conclusions [260] . The negative results of the supplementation of PUFA in manifest MS however, do not exclude some preventive ef ﬁ cacy [261] .

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Recommendation 36:

We recommend suf ﬁ cient dietary vitamin D intake and adequate sunlight exposure that ensures adequate vitamin D levels for the prevention of MS. In cases of low vitamin D intake, low sunlight exposure and subsequent low levels of vitamin D, dietary supplementation is recommended.

Grade of recommendation: B e strong consensus (91% agreement)

Commentary:

The hypothesis that MS is associated with low sunlight exposure and subsequently low vitamin D3 levels was based at ﬁ rst on the geographical variability of its prevalence [262 e 264] . Furthermore, epidemiological studies have suggested a link between sunlight and vitamin D3 and MS [265] , a ﬁ nding that has been corroborated in observational and case e control studies. More speci ﬁ cally, in a study on 187,563 women in USA, the risk of MS was inversely associated with the vitamin D intake by supplements, a relationship which failed to reach signi ﬁ cance when vitamin D from food was assessed [266] . This association was further con ﬁ rmed in a case e control study of 148 cases and 296 controls where 25- hydroxyvitamin D3 plasma concentrations were inversely associated with the MS risk, particularly if the levels had been low before the age of 20 years [260,264] .

Recommendation 37:

We do not recommend vitamin B12 supplementation as a way to prevent MS.

Grade of recommendation: 0 e strong consensus $\mathbf{\{95\%}}$ agreement)

Commentary:

It is well established that vitamin B12 de ﬁ ciency causes neurodegeneration of sensory and motor neurons, a condition that is reversed when de ﬁ ciency is corrected. Above that, no neuroprotective effects of vitamin B12 supplementation have been documented. Moreover, the hypothesis linking MS and vitamin B12 de ﬁ ciency has not been con ﬁ rmed [260,267] .

Recommendation 38:

We do not recommend vitamin C supplementation as a way to prevent MS.

Grade of recommendation: B e strong consensus $\mathbf{\{95\%}}$ agreement)

Commentary:

Ascorbic acid is a well-known antioxidant, protecting cells against oxidative stress. High levels of vitamin C intake though have not been proven bene ﬁ cial neither for neurodegenerative nor cardiovascular diseases [260] .

Recommendation 39:

A gluten free diet in order to prevent MS is not recommended.

Grade of recommendation: B e strong consensus ( $\bf{100\%}$ agreement)

Commentary:

The connection of gluten and MS was mainly based on the hypothesis that gluten hypersensitivity may contribute to neuroimmunological diseases based on results of brain magnetic resonance imaging (MRI) from celiac disease patients that had similarities with MS patients [260] . This hypothesis though was not supported by further studies, in which neither the anti-gliadin antibodies nor morphological changes in the gut mucosa were reported in patients with MS [268 e 270] . Furthermore, the withdrawal of gluten containing foods from the diet of MS patients was not found to have any signi ﬁ cant positive effect [271] .

Recommendation 40:

Prevention of obesity in adolescence and early adulthood is recommended for the prevention of MS.

Grade of recommendation B e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Overweight and obesity during adolescence and early adulthood seem to contribute to overall risk of development MS. Excess adipose tissue may have a negative impact on vitamin D metabolism and bioavailability, resulting in lower blood levels of 25(OH) vitamin D levels in obese compared to healthy individuals [272,273] . In the Nurses' Health Studies (NHS/NHSII) it was reted those women who were obese at the age of 18 $(\mathrm{BM}\geq30\,\mathrm{kg}/$ $\mathfrak{m}^{2\cdot}$ ) had a two-fold increased risk of developing MS compared to women with BMI between 18.5 and $20.9\,\mathrm{kg}/\mathrm{\bar{m}}^{2}$ ( $\mathtt{R R}=2.25$ , 95 %CI: 1.5 e 3.37). Obesity in younger ages also was correlated with increased risk of MS but after adjusting for body size at these ages the signi ﬁ cance remained for women being obese at the age of 20 years $\mathbf{\tilde{R}R}=1.96$ , 95 %CI:1.33 e 2.89) [274] . Concluding, obesity in adolescence and early adult life may increase the risk of MS and its prevention may contribute to the reduction of its risk [275,276] . See supplementary data for Clinical Question 25 .

5.2. Clinical Question 26: Can medical nutrition therapy decrease the rate and severity of relapses in MS patients?

Literature review regarding this topic focused the attention on the role of some vitamins, specially vitamin D and omega fatty acids as potential modulators of the disease.

Recommendation 41:

There is insuf ﬁ cient evidence to recommend vitamin D therapy in MS patients. There is no clinical evidence on the effects of either vitamin D compared with placebo or high-dose vitamin D compared to low-dose on the relapse rate of patients with MS.

Degree of recommendation: B e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

In the latest years, the relation between vitamin D and MS has generated an enormous interest. The relationship between geographical differences in the prevalence of MS, sun exposure and vitamin D metabolism have been studied. Relapses of the disease occur more frequently in winter when vitamin D levels are lower.

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Vitamin D exerts many immunomodulatory effects, increases lymphocyte proliferation and reduces the production of proin ﬂ ammatory cytokines. In the epidemiological study USAmerican Nurses' Health Study [277] , women who took vitamin D supplements had a lower risk of MS, although it is dif ﬁ cult to extract the results due to other vitamins in the diet or vitamin supplements. Ascherio et al. [278] demonstrated, in a large multicenter randomized trial designed to evaluate the impact of earlyversus delayed-interferon beta-1b treatment in patients after a ﬁ rst event suggestive of MS, that higher levels of 25-vitamin D predicted reduced MS activity (relapses and disability) and led to a slower rate of progression at 24 months.

Unfortunately, the studies that evaluate the effect of vitamin D are prone to many sources of bias (selection bias due to diet or sun exposure, reverse causation due to the disease, and effect of the skin type or genetic factors) [279,280] .

One National Guideline (NICE) has addressed the topic of the clinical evidence of pharmacological treatment of vitamin D in patients with MS [281] . A recent systematic review of the literature has also been published [282] . Four studies have assessed the effect of vitamin D versus placebo on the disease relapses over follow-up time or on the annualized relapse rate [283 e 286] .

Burton et al. [284] assessed, in an open-label 52-week duration RCT, the effects of high doses of vitamin D (40.000 IU/day for 28 weeks, followed by 10.000 IU/day over 28 weeks). After the trial, mean annualized relapse rate in treatment patients decreased although the results were not statistically signi ﬁ cant. The proportion of treatment patients experiencing relapses during the trial was 0.16 vs 0.37 in the control group $\mathbf{\check{p}}=0.09)$ .

Shaygannejad et al. [283] studied the effect of low dose vitamin D in combination with current disease-modifying therapy on the prevention and progression of relapsing-remitting MS, in a doubleblind placebo-controlled study including consecutive 50 patients. They were randomized to receive 12 months escalating doses of calcitriol up to $0.5\;\upmu\mathrm{g}/$ day or placebo. They de ﬁ ned acute relapse as the appearance of a new neurological symptom or severe deterioration in a preexisting symptom that lasted for at least $24{\mathrm{~h~}}$ in the absence of fever/infection and caused an increase of at least 1 point in the Expanded Disability Status Scale (EDSS). After the trial, the mean relapse rate decreased signi ﬁ cantly in both groups. The authors concluded that there is no evidence of an effect on the odds of remaining relapse-free during the ﬁ rst 12 months of therapy in patients who received vitamin D compared to those who received placebo.

Kampman et al. [285] performed a 96-week RCT to assess the effect of vitamin D3 supplementation (20.000 IU weekly) or placebo on bone mineral density in 68 patients with MS. As a secondary endpoint, they assessed the effect on annualized relapse rate. After the trial, there was no signi ﬁ cant difference between groups in annualized relapse rate (absolute difference 0.10, $95\%$ CI ' 0.07 e 0.27, ${\tt p}=0.25$ ). The authors concluded that supplementation with 20.000 IU vitamin D3 weekly did not result in bene ﬁ cial effects on the relapse rate in MS patients.

Soilu-H anninen et al. [286] evaluated the effect of 20.000 IU of vitamin D3 weekly for 1 year in a double blind, placebo-controlled randomized trial including 66 MS patients treated with interferon $\upbeta$ -1b for at least 1 month. The primary endpoint was disease activity measured by MRI scan. As a secondary endpoint, they assessed the annual relapse rate in both groups. After the trial, the annual relapse rate decreased during the study in both treatment arms (from 0.49 to 0.26 in the vitamin D group, and from 0.51 to 0.28 in the placebo group, $\mathsf{p}=\mathsf{N S},$ ). There was no signi ﬁ cant difference in the time to the ﬁ rst relapse between groups. The proportion of relapses treated with methylprednisolone was similar in both treatment arms.

Two studies have evaluated the effect of high dose vitamin D versus low dose vitamin D [287,288] .

Stein et al. [287] compared in a 6 months' double-blind placebocontrolled high-dose vitamin D2 (6.000 IU targeting 25-OH vitamin D 130 e 175 nM) with 1.000 IU daily vitamin D2. The primary endpoint was new MRI lesions, and as a secondary endpoint, relapse rate was evaluated. They included 23 patients in the trial, of whom 19 were on disease-modifying drugs (interferon or glatiramer). No signi ﬁ cant differences were detected either in the primary endpoint, or in relapse rate during the trial (there were 4 relapses with high-dose D2 vs none with low-dose D2, ${\tt p}=0.04$ )

Golan et al. [288] assessed the effect of 800 IU of vitamin D3 per day vs 4.370 IU/day in a randomized, double blind study including $45\,\mathrm{{IPN}\upbeta}$ -treated MS patients during one year. The primary endpoint was the control of ﬂ u-like symptoms, and as a secondary endpoint, they assessed relapse rate of the disease. Both groups were similar at baseline with respect to relapses and annualized relapse rate during the year preceding randomization. At the end of the study, no differences were found in the annual relapse rate in both groups.

One systematic review of six trials [289] reported that no studies had results suggestive of a bene ﬁ t of vitamin D supplementation for reducing relapse rates in MS patients. Another systematic review and meta-analysis [290] reported that there was no signi ﬁ cant difference in the pooled odds of relapse between high dose vitamin D supplements and low dose or placebo.

In conclusion, the RCT published to date investigated the use of vitamin D supplements of various doses and formulations and with or without concomitant therapy for MS treatment and with calcium supplements. The duration of treatment also varied between trials.

Recommendation 42:

Supplementation with omega-3 fatty acids should not be recommended in MS patients to decrease the number and severity of relapses. Supplementation with omega-6 fatty acids could be of some possible bene ﬁ t in terms of decreasing the number and severity of the relapses.

Degree of recommendation: 0 e strong consensus (100% agreement)

Commentary:

The hypothesis that a change in dietary fat can modify the course of MS is based on epidemiological and experimental studies. MS is more prevalent in populations with a high intake of saturated fats. Furthermore, PUFA, particularly omega-3 fatty acids have an immunomodulatory and anti-in ﬂ ammatory role that could in ﬂ uence the course of the disease. The intake of omega-3 fatty acids from ﬁ sh oil can reduce the production of pro-in ﬂ ammatory prostaglandins and leukotrienes derived from arachidonic acid.

Until now, non-controlled and controlled clinical trials of PUFA supplementation in patients with MS have provided mixed results. These studies have important limitations in design and selection of outcome measures, and these factors might partially explain the inconsistent results [259 e 261] . The inclusion of both patients with relapsing MS and patients with chronic, progressive disease provides another important bias in the results of any nutritional treatment in the relapses of MS. The selection of the placebo is also a matter of discussion. Some PUFA intervention studies used olive oil as a placebo, and evidence demonstrates that oleic acid is not an inert substance. Also, recently published NICE Guidelines assessed the clinical evidence of omega-3 and omega-6 fatty acids [281] on the evolution of MS patients.

Omega-6 fatty acids: Some authors have reported low levels of linoleic acid in blood, in the erythrocyte membrane and

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cerebrospinal ﬂ uid of MS patients. There have been several small placebo-controlled studies evaluating intervention with [261] linoleic acid (obtained from sun ﬂ ower oil). Although studies have been conducted with small samples, none of them has been shown any effect on relapse rate or degree of disability [291] . In a metaanalysis including 3 studies with 87 patients and 85 controls, some bene ﬁ t was observed in the group of patients with moderate disabilities or short disease duration at baseline, in terms of reduced disability progression and reduced severity and duration of relapses [292] . The results in the group of severely disabled patients are not as consistent. A 2012 Cochrane review [293] including 6 randomized controlled trials investigating PUFAs effect on disease progression assessed 794 patients, and theyconcluded that PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), but they may tend to reduce the frequency of relapses over two years. However, the data that are available are insuf ﬁ cient to assess a real bene ﬁ t or harm from PUFA supplementation.

Omega-3 fatty acids: docosahexaenoic acid (DHA) is present at high concentration in the brain, but its levels decrease in MS patients. Both eicosapentaenoic acid (EPA) and DHA are found in high proportion in ﬁ sh oil and show remarkable anti-in ﬂ ammatory, antithrombotic and immunomodulating activities and also exert important effects on gene expression. For this reason, n-3 fatty acids exert a number of neuroprotective effects. There are insuf ﬁ - cient data to con ﬁ rm any bene ﬁ cial effect of omega-3 fatty acids in patients with MS, although some studies with small samples have shown some promising results. In a large intervention study with 292 patients randomized to take ﬁ sh oil ( $1.7\,\mathrm{g}$ of EPA and DHA $1.1\;\mathrm{g}$ per day) or olive oil as placebo, no signi ﬁ cant differences were found between the two groups with regard to the frequency, duration or severity of relapses [294] . See supplementary data for Clinical Question 26 .

5.3. Clinical Question 27: Does medical nutrition therapy improve nutritional status in MS patients?

Recommendation 43:

We recommend early detection and treatment of the causes of malnutrition by a multidisciplinary team in patients with MS. Grade of recommendation: GPP e strong consensus $\mathbf{\cdot100\%}$ agreement)

Recommendation 44:

We strongly recommend the provision of dietary advice for the prevention and treatment of nutritional problems in patients with MS. In patients unable to meet their nutritional needs by food intake the use of oral nutritional supplements should be considered.

Grade of recommendation B e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

Unintentional weight loss and malnutrition are common in patients with MS, even though the data regarding malnutrition prevalence and its treatment in patients with MS are scarce [295,296] . One of the most important cause of malnutrition in MS patients is dysphagia, limiting nutritional intake and deteriorating nutritional status of the patients [251] .

Malnutrition has also been shown to impair immune system and strength, to induce fatigue and impair muscle function, affecting mental function, respiratory muscle strength and increase

the risk of infections. The prevention of malnutrition is of vital importance in patients with MS as it can compound existing symptoms, such as muscle dysfunction, fatigue and muscle spasms [295] . According to a Cochrane review the evidence supporting the effectiveness of interventions on the management of fatigue and/or weight loss in advanced stages of progressive illnesses such as MS are lacking [297] . Nevertheless, the adequate provision of nutrients by diet and/or medical nutrition therapy should be considered in patients with MS in order to prevent and correct malnutrition and nutrient de ﬁ ciencies.

Nutritional screening and assessment of the nutritional status of the patients with MS with appropriate screening and assessment tools is necessary, with the input of the patient and the caregivers. Medical nutrition therapy in patients with MS requires a multidisciplinary approach. The participation of a neurologist, a nutritionist/dietitian, a speech and language therapist for the evaluation of swallowing ability, physiotherapist for the evaluation of eating posture, occupational therapist to evaluate the need of speci ﬁ c cutlery and a nurse is of vital importance in order to perform a comprehensive evaluation of the etiology of malnutrition in order to ensure the early detection of problems affecting suf ﬁ cient nutrient intake [251,295] . The ef ﬁ cacy of dietary advice has been evaluated in several systematic reviews for the treatment of disease related malnutrition. Dietary advice alone or with ONS may improve weight, body composition and muscle functionality, even though no positive results on survival by either interventions was observed [298 e 300] .

Although there is a lack of trials focusing on the effectiveness of ONS on nutritional status of malnourished patients with MS, the ef ﬁ cacy of ONS in chronic illness in the community and hospital setting has been evaluated by several systematic reviews [298,299,301,302] . ONS use in the community has been identi ﬁ ed as a cost-effective way of treating malnutrition, producing a neutral or an overall cost advantage, in combination with clinically relevant outcomes [302,303] . See supplementary dataforClinical Question 27 .

5.4. Clinical Question 28: Can medical nutrition therapy improve survival in MS patients?

Recommendation 45:

We have no direct evidence about the effect of medical nutrition therapy on survival in MS patients. More research is needed to answer this gap of knowledge.

Grade of recommendation: GPP e strong consensus ( $\bf{100\%}$ agreement)

Commentary:

To date, there is no RCT that has assessed the in ﬂ uence of medical nutrition therapy in the survival of malnourished patients with MS that cannot meet their nutritional requirement with their usual diet. Some authors have evaluated prognostic factors for mortality in MS patients. Chruzander et al. [304] evaluated in a population-based study in Stockholm, the effect of some personal and disease-speci ﬁ c factors on mortality at 10 years' follow-up, and they detected higher age at diagnosis $_{\textrm{\tiny(>51y)}}$ , progressive disease course and depressive symptoms as negative prognostic factors for survival. Similar results are con ﬁ rmed by Kinqwell et al. [305] with regard to age at diagnosis and progressive form of the disease. Scalfari [306] analyzed data of published large cohorts' registries, and also found higher age at diagnosis as a negative prognostic factor for mortality. None of the mentioned studies analyzed any nutritional data as a

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prognostic factor for mortality in MS patients. From indirect data, some authors have found that respiratory infection and sepsis are the most frequent MS-related causes of mortality [307] , and we can hypothesize that dysphagia and or malnutrition can be involved as a causative factor. However, there is a lack of intervention studies to demonstrate the effect of medical nutrition therapy on survival in MS patients.

5.5. Clinical Question 29: Are there speci ﬁ c methods for screening and clinical diagnosis of OD in MS?

Dysphagia is a common symptom in MS patients, and can be the consequence of several potential factors such as involvement of the corticobulbar tracts, cerebellar and brainstem dysfunctions, lower cranial nerves paresis and cognitive impairment, all of which can impair swallowing physiology. Dysphagia can cause severe morbidity in MS patients, increasing the risk of dehydration and aspiration pneumonia and reducing the quality of life and increasing mortality. Prevalence of dysphagia in patients with MS ranges between 10 and $90\%$ of patients, depending on the method used to evaluate the swallowing problem and the population included in the study. A recent meta-analysis [10] showed that the pooled prevalence of 12 studies using subjective methods (different dysphagia questionnaires and only one water swallowing questionnaire) is of 36% ( $95\%$ CI 31 e 42). However, the pooled prevalence of objective methods (instrumental measurements, 3 studies VFS and one study FEES) is of $81\%$ . Nevertheless, there was substantial heterogeneity across subjective and objective prevalence estimate. Several studies reported that the prevalence of dysphagia was related to the disability and the duration of the disease [11,308,309] , while other studies reported that dysphagia can be present in MS patients with an Expanded Disability Status Scale lower than 2.5 (low disability) [310] .

Recommendation 46:

MS patients should be screened for dysphagia early in the course of the disease, especially if they have cerebellar dysfunction. The screening should be repeated at regular intervals depending on clinical situation. We have not enough evidence to recommend one speci ﬁ c screening method for dysphagia in this population.

Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 47:

MS patients should be screened routinely for dysphagia over the course of the disease, although we have not suf ﬁ cient evidence to recommend the timing. Patients with severe disabilities, cerebellar dysfunction and long disease duration are the highest risk patients.

Grade of recommendation: GPP e strong consensus (96% agreement)

Recommendation 48:

Instrumental exploration of dysphagia should be performed in MS patients with high risk for dysphagia (severe disabilities, cerebellar dysfunction and long disease duration), or dysphagia symptoms. We have not suf ﬁ cient evidence to recommend one speci ﬁ c method for diagnosis.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

Clinical screening of dysphagia: A clinical questionnaire to detect patient-reported dysphagia in MS patients was designed by Bergamaschi et al. [311] : the Dysphagia in Multiple Sclerosis (DYMUS) questionnaire. The survey includes 10 questions that allow the assessment of dysphagia for solids and liquids. DYMUS questionnaire was initially performed in a cohort of 226 consecutive outpatients and later validated in a very large group of consecutive MS patients during routine checkups outside relapses [312,313] . It identi ﬁ ed $92\%$ of patients complaining for swallowing problems. In asymptomatic patients, the DYMUS questionnaire identi ﬁ ed $14\%$ of patients that should be subjected to further, more speci ﬁ c investigations. The questionnaire was abnormal in $31\%$ of patients. The patients that reported dysphagia with the test had higher EDSS score and longer disease duration. The results of the DYMUS questionnaire correlated positively with the penetration e aspiration scale measured by FEES in a small group of consecutively hospitalized MS patients [314] . To date, the DYMUS questionnaire has not been formally validated with an instrumental tool to evaluate the sensitivity and speci ﬁ city of dysphagia in MS patients.

Other bedside clinical tests for the assessment of dysphagia are not validated speci ﬁ cally for screening of dysphagia in MS patients. Clav e et al. [79] only included 4 MS patients in their validation of the volume-viscosity swallow test. De Pauw et al. [308] reported the results of the questionnaire of the Johns Hopkins Swallowing Centre in 68 of 73 MS patients with permanent dysphagia (de ﬁ ned as dysphagia outside an acute relapse), and they found that the most frequent symptoms were altered feeding habits $(92\%)$ , coughing and choking during meals $(58\%)$ , food sticking in throat $(32\%)$ and dif ﬁ culty managing secretions $(32\%)$ . Twelve per cent of patients had history of pneumonia. Levinthal et al. [315] explored dysphagia prevalence using the MD Anderson dysphagia inventory in a cohort of 218 consecutive patients recruited to participate either during routine follow-up clinic visits or during scheduled visits for drugs infusions, and reported a prevalence of dysphagia in $20\%$ of patients. The swallowing functions of 101 consecutive MS patients were screened by the Northwestern Dysphagia Patient Check Sheet by Poorjavad [252] and $31.7\%$ were classi ﬁ ed as having dysphagia. Pharyngeal stage disorders were the most common observed impairment $(28.7\%)$ and aspiration, oral stage disorders, and pharyngeal delay were observed in $6.9\%$ , $5\%$ , and $1\%$ of patients, respectively. Patients with dysphagia had signi ﬁ cantly longer disease duration, more neurological impairment in cerebellar functional system and more neurological disability as measured by ESSD scores. Thomas et al. [316] explored dysphagia in a group of 79 MS patients consecutively admitted to the hospital using a water test ${'150\;\mathrm{{mol}}})$ ), and found positive screening for dysphagia in $43\%$ of patients. Abnormal swallowing was associated with several factors including abnormal brainstem/cerebellar function, disability, vital capacity, and depression score.

Instrumental diagnosis: Clacagno et al. [11] reported the results of FEES in 143 consecutive patients with primary and secondary progressive MS who underwent for neurological rehabilitation, and they found dysphagia in $34\%$ of patients. In this study, dysphagia risk was related with severe brainstem impairment (OR 3.24; $95\%$ CI 1.44 e 7.31) as compared with patients without severe brainstem impairment. Severity of the illness was also associated with risk of dysphagia (OR 2.99, CI 1.36 e 6.59), but not with duration of the disease. Fernandes et al. [317] explored a cohort of 120 MS patients with FEES, and they reported a $90\%$ prevalence of dysphagia, more frequent in secondary progressive and primary progressive forms of the disease, and related with involvement of cerebellar, brainstem and mental functions on the Functional Disability Scale and also

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with worse Expanded Disability Status Scale (EDSS) scores. The study of Alfonsi [314] found a $53\%$ of abnormal FEES in a cohort of 26 MS patients. De Pauw et al. [308] explored with mano ﬂ uoroscopy 30 of the 73 MS patients with permanent dysphagia in their study, and they described de ﬁ ciency of the oral phase in all patients, while only the patients with an EDSS higher than 7.5 showed abnormalities of the pharyngeal phase (mostly hypopharyngeal hypocontractility and reduced opening of the upper esophageal sphincter).

Two studies explored dysphagia with VFSS in MS patients. Wiesner et al. [318] found video ﬂ uoroscopic abnormalities in $55\%$ of 18 consecutive MS patients, including $75\%$ of patients absolutely asymptomatic with regard to swallowing. Terr e-Boliart et al. [319] reported a prevalence of $83\%$ of VFSS abnormalities in 23 MS patients controlled in a neurorehabilitation unit. In $52\%$ of patients with dysphagia there was some change in the swallowing safety, and $40\%$ of them were silent aspirators. Electrophysiological evaluation of dysphagia has been performed by Alfonsi [314] and Beckmann [320] in 26 and 51 patients, respectively. They found a high prevalence of electrophysiological abnormalities in asymptomatic patients (subclinical dysphagia), that can be unmasked performing a sequential water swallowing test during electrophysiological evaluation of swallowing. Electrophysiological evaluation of dysphagia can be a promising exploration to detect early dysphagia. All these results emphasize the importance of assessment and management of swallowing function in MS patients, particularly in patients with a high EDSS score, more severe cerebellar dysfunction, and long disease duration. See supplementary data for Clinical Question 29 .

5.6. Clinical Question 30: What are the effects of behavioral, rheological and rehabilitation treatments for OD in patients with MS?

Recommendation 49:

We recommend in MS patients with dysphagia the use of modi ﬁ ed consistency foods and ﬂ uids to ensure safe swallowing, according to the individualized needs of the patients.

Grade of recommendation GPP e strong consensus $\mathbf{\left(96\%\right.}$ agreement)

Recommendation 50:

No disease speci ﬁ c recommendation can be provided for the behavioral treatment of dysphagia in patients with multiple sclerosis due to lack of evidence. Therefore, general recommendations for dysphagic patients should be followed.

Grade of recommendation GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Recommendation 51:

We recommend EN therapy in dysphagic patients unable to cover their nutritional needs orally. In patients with MS and other chronic neurological disorders PEG should be chosen as a method of delivery of EN.

Grade of recommendation B- strong consensus $\mathbf{\{96\%}}$ agreement)

Commentary:

Dysphagia in multiple sclerosis has been found to be more frequent than it was previously thought, affecting almost one third of the patients [10,308] . Permanent dysphagia may already develop in mildly impaired MS patients but becomes a rather frequent

ﬁ nding in MS patients with moderate or severe disability [308] . Dysphagia is a serious condition, affecting the ability of the patient to fully cover his nutritional needs and could be potentially hazardous as it is related to fatal complications such as aspiration pneumonia and severe malnutrition [321] .

Interventions for neurogenic dysphagia are mainly based on functional swallowing therapy, including methods of restitution, compensation and adaptation. The aims of the interventions are to help patients maintain their nutritional status and most importantly to prevent aspiration and aspiration pneumonia [322] . Data regarding the effectiveness of behavioral, rheological and rehabilitation treatments for OD in patients with MS are limited. Studies evaluating the ef ﬁ cacy of interventions in MS patients either include a very small sample size of patients or are pilot studies, limiting their signi ﬁ cance for formulating safe recommendations regarding the ef ﬁ cacy of interventions for the management of dysphagia in MS patients. Nonetheless, in patients with neurodegenerative diseases and dysphagia of neurological etiology, training in swallowing with triggering of re ﬂ exes, training of swallowing process and adjustment in the consistency of the food and liquids can help to improve the process of swallowing, help maintain suf ﬁ cient nutritional intake and reduce the risk of aspiration [295,323] .

Data regarding the effectiveness of thickened ﬂ uids or modi ﬁ ed consistency foods are very scarce in MS patients, based not on randomized trials but on quanti ﬁ ed examinations of the swallowing ability with or without the use of thickeners or different types of consistencies of food items [226,227] . Nonetheless, the use of thickened ﬂ uids is a common strategy to improve swallowing safety in a variety of oropharyngeal dysphagic patients, including those who cannot suf ﬁ ciently control the swallowing of thin liquids or when airway protection is disturbed during swallowing [324,325] .

PEG is one of the most commonly used methods for enteral nutrition in patients who are unable to take food orally [326,327] . The most common indication is neurogenic dysphagia, followed by obstructive causes such as head and neck tumors. PEG is the route of choice for enteral nutrition in chronic neurological patients unable to feed themselves safely orally, as it is well tolerated and can lead to a signi ﬁ cant improvement of nutritional status [328] . See supplementary data for Clinical Question 30 .

6. Stroke

Stroke is one of the most prevalent acute neurological diseases and one of the world's leading causes of mortality and physical disability in adults. The risk of stroke increases with age. Other identi ﬁ ed known risk factors for stroke are hypertension, cigarette smoking, heart disease, diabetes, transient ischemic attacks, lack of exercise, alcohol, diet and obesity. According to the World Health Organization, the number of stroke events in EU countries, Iceland, Norway, and Switzerland is likely to increase from 1.1 million per year in 2000 to more than 1.5 million per year in 2025, solely because of the demographic changes [329] . Currently 6 million subjects live in these countries having survived a stroke. Approximately one-third of individuals who recover from their ﬁ rst stroke will have another stroke within 5 years. Recurrent stroke is a major contributor to disability and death. The global cost of stroke in Europe is estimated as high as 64 billion Euros [330] .

Stroke patients are prone to malnutrition and dehydration mainly due to dysphagia, impaired consciousness, perception deficits and cognitive dysfunction. Being malnourished or at risk of malnutrition on admission is associated with an increased risk of mortality and poor outcome [331] . Furthermore, nutritional status can worsen during the ﬁ rst week after a stroke [332,333] . Stroke patients are also at high risk for aspiration pneumonia, a lifethreatening complication with very high mortality. Early

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detection and treatment of dysphagia would be a cornerstone in the management of stroke patients in order to decrease the incidence of malnutrition, dehydration and aspiration pneumonia. Several clinical questions arise about medical nutrition therapy in patients who have had a stroke.

6.1. Clinical Question 31: Which stroke patients should be screened and assessed for dysphagia?

Recommendation 52:

A formalized screening for dysphagia should be performed in all stroke patients as early as possible and before oral intake.

Grade of recommendation B e strong consensus $\mathbf{\{95\%}}$ agreement)

Recommendation 53:

All stroke patients failing the dysphagia screening or demonstrating symptoms of or risk factors for dysphagia should be evaluated with a more thorough assessment of swallowing function as early as possible.

Grade of recommendation B e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Commentary:

Dysphagia affects at least $50\%$ of patients with ischemic or hemorrhagic stroke [4,5] . In the acute stage of stroke aspiration pneumonia is the most important complication of dysphagia. Adjusted for other risk factors dysphagia more than doubles the risk for this complication [3] . Pneumonia in turn is associated with increased mortality, length of hospital stay, dependency at discharge and institutionalization [334,335] . Several studies have demonstrated that a formalized dysphagia screening and assessment is capable to reduce the rate of pneumonia [19,336 e 346] . In particular, the prospective registry-based cohort study by Bray et al. has demonstrated in 63,650 stroke patients that any delay in dysphagia screening and comprehensive dysphagia assessment leads to an increase in stroke-associated pneumonia in a strong time-dependent manner [347] . Therefore, screening and if necessary assessment for dysphagia should be performed as early as possible. The diagnostic approach starts with a formal aspiration screening, which may be a water swallow test [348 e 350] or a multi-consistency-test [351 e 354] .

If a patient fails the screening or demonstrates signs of dysphagia, such as coughing, choking, wet voice, food-residuals in the mouth or pneumonia outside the screening test, a more thorough assessment has to be performed [350,355] . The same is true if the screening is negative, but risk factors for dysphagia such as dysarthria, aphasia, facial palsy, cognitive impairment, decreased level of consciousness and high stroke severity are present [349,356 e 359] . The more severe the stroke, the higher is the probability of dysphagia. In fact a National Institute of Health stroke scale of 10 and above demonstrated a high sensitivity and speciﬁ city in predicting dysphagia [360,361] .

When it comes to a more comprehensive assessment, a clinical bedside assessment (CBA) performed by a speech and language therapist, a VFS or a FEES can be performed. Since the diagnostic properties of the CBA have been less well explored and questioned recently, instrumental testing should be preferred [179] . As a bedside method, FEES includes several advantages and needs only minimal cooperation of the patient. Therefore, it is predestined to be utilized as an assessment method in stroke patients. A study by Bax et al. could suggest that access to FEES was associated with a

signi ﬁ cantly reduced rate of pneumonia after stroke [339] . See supplementary data for Clinical Question 31 .

6.2. Clinical Question 32: Does a routine screening of nutritional risk compared with standard care lead to lower morbidity and mortality or improve other outcomes in acute stroke patients?

Recommendation 54:

The available evidence suggests that all stroke patients should be screened for risk of malnutrition on admission to hospital (within 48 h), and the MUST can be used to identify patients who are more likely to bene ﬁ t from medical nutrition therapy.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

When compared to a normal nutritional status, malnutrition is associated with a worsened outcome in terms of increased mortality, length of hospital stay and hospitalization costs. The association between nutritional status and mortality was analyzed in a large cohort of 3012 patients with a recent stroke enrolled in the Feed Or Ordinary Food (FOOD) trial [332] . The 6-month mortality was higher in the group of 275 patients deemed malnourished, using a variety and often non-validated criteria, than in patients with normal nutritional status (37 vs $20\%$ ). These ﬁ ndings were con ﬁ rmed recently using a formal nutritional screening tool in 543 patients with acute stroke. Using the Malnutrition Universal Screening Tool (MUST) to evaluate the risk of malnutrition within 48 h post stroke, from low to high, the authors found a 6-month mortality rate increasing from 6 to $42\%$ [331] . Likewise, in this study, the length of hospital stay (LOS) and related costs increased as the risk of malnutrition rose from low to high. In fact, risk of malnutrition was able to predict the 6-month mortality, LOS and costs (related to the ﬁ rst and recurrent hospital admissions during the follow-up period) independently of age, gender, ethnicity, type of stroke, stroke severity and several stroke risk factors. This was the ﬁ rst study that validated a nutrition screening tool in the stroke population and its predictive validity suggests that MUST is a tool that can be used on stroke patients to identify those who are more likely to bene ﬁ t from medical nutrition therapy. In two other recent studies, pre-stroke underweight or weight loss were associated with increased 30-d post-stroke mortality [362,363] .

A few studies have failed to clearly demonstrate clinical beneﬁ cial effects of medical nutrition therapy in stroke patients [21] . This may be explained by the fact that many of those studies have not used nutrition screening or assessment tools validated for the stroke population, therefore they may have missed those who were more likely to bene ﬁ t from nutritional therapy. See supplementary data for Clinical Question 32 .

6.3. Clinical Question 33: Does individual dietetic counseling compared to standard care lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with nutritional risk?

Recommendation 55:

Patients who are malnourished or at risk of malnutrition should receive medical nutrition therapy through an individual nutrition care plan. Whenever possible, a nutrition specialist should develop and monitor this plan.

Grade of recommendation: B e strong consensus (91% agreement)

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Commentary:

The majority of the studies [21] which have explored the effect of medical nutrition therapy strategies for stroke patients (some of them conducted in individuals who are malnourished or at risk of malnutrition) tend to provide an undifferentiated form of medical nutrition therapy for all the individuals of the intervention group, e.g. using only oral nutritional supplements for patients without swallowing problems. Only one study has evaluated the effect of an individualized nutrition treatment plan in this population, involving different forms of medical nutrition therapy according to the individual needs of each patient.

Ha and her colleagues [364] selected a group of hospitalized acute stroke patients aged $>65$ years who were assessed as being undernourished (using anthropometric values) or at nutritional risk (using a modi ﬁ ed version of the Malnutrition Universal Screening Tool). These patients were allocated to the intervention group, where they received an individualized nutritional treatment plan detailing type, amount and route of feeding (including oral nutritional supplements and enteral tube feeding) for each patient, or to the control group, where patients received routine care at the discretion of the attending physician. In the intervention group, the nutrition plan was adjusted as necessary, according to the recorded and calculated dietary intake for each patient, and individual advice to prevent malnutrition was delivered before discharge. Outcomes were assessed at 3 months after study entry. Results showed statistically signi ﬁ cant differences between the groups in favor of the intervention group with regards to energy intake [5010 (SD 1376) kJ/day versus 4373 (SD 1268) kJ/day; $\mathrm{P}=0.032,$ ), as well as change in weight $\it{(20.7\%}$ versus $36.4\%$ had ${\geq}5\%$ weight loss; $\mathsf{P}=0.055)$ and handgrip strength (2.3 (SD 3.7) versus ' 0.3 (SD 4.9) kg; $\mathbf{P}=0.002.$ ), and some domains of the quality of life questionnaire (i.e. mobility, self-care and usual activities domains) although one quarter of these questionnaires were incomplete. There was no difference in length of hospital stay between groups.

Another two papers from the same author and using the same cohort of patients were found [365,366] . In the study that analyzed the body composition of this cohort of patients [365] , the group that received the individualized nutritional treatment plan suffered less from unintentional weight loss in the ﬁ rst week of hospitalization, and the intervention subgroup of women had a smaller loss of body fat at 3 months, when compared with the control subgroup of women. The long term mortality (5 e 7 years post stroke) for this cohort was later analyzed [366] and results showed no statistically signi ﬁ cant difference in this outcome between both groups. It should be noted that the nutritional intervention was delivered for a relatively short period of time (i.e. only during hospitalization, and advice to prevent malnutrition was given prior to discharge), therefore it remains unclear whether the long-term outcomes would have been in ﬂ uenced by a longer period of medical nutrition therapy. Larger and good quality RCTs, providing medical nutrition therapy for a longer period of time to patients identi ﬁ ed at risk of malnutrition using a validated nutrition screening tool, will help to ﬁ ll this gap in the evidence.

In summary, the existing evidence suggests that medical nutrition therapy, given through an individualized nutritional treatment plan tailored to the speci ﬁ c needs of the patient, can help to meet energy requirements and prevent weight and fat loss, and can also contribute to improvement of functional status and quality of life. Stroke patients are particularly vulnerable to malnutrition, and this is a complex problem that may require multiple strategies to ensure that the nutritional needs of the patients are met, to prevent further catabolism and to maximize the potential for rehabilitation. A nutrition specialist (e.g. a dietitian or a nutritionist with experience in stroke) gathers the skills required to understand

the multiple causes of malnutrition or the factors that place the patient at risk of malnutrition, and is well positioned within the multidisciplinary team to develop and monitor a nutrition care plan tailored to the speci ﬁ c needs of the patient. Therefore, it is recommended that, whenever possible, a nutrition specialist should develop and monitor the individual nutrition care plan. See supplementary data for Clinical Question 33 .

6.4. Clinical Question 34: Do oral nutritional supplements compared to standard care lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with nutritional risk?

Recommendation 56:

Routine ONS are not recommended for patients with an acute stroke without dysphagia and who are adequately nourished on admission.

Degree of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 57:

In stroke patients who are able to eat and who have been identi ﬁ ed to be malnourished or at risk of malnutrition ONS are recommended.

Degree of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

In the acute phase of stroke, $30{-}50\%$ of patients suffer from dysphagia, while the incidence drops to around $10\%$ at six months of acute stroke. Dysphagic stroke patients are prone to dehydration and malnutrition, and also have an increased risk of aspiration pneumonia and global mortality. The relevance of an early detection of malnutrition and dysphagia is well de ﬁ ned, but there are few studies on the effect of ONS in stroke patients who are able to eat and who have been identi ﬁ ed as malnourished or at risk of malnutrition [19 e 21] . In the overall group of stroke patients without dysphagia, ONS do not improve survival or functional outcome, and only some positive results have been demonstrated in patients clearly identi ﬁ ed as malnourished. There are very few studies focusing on this topic in the literature.

Gariballa [367] and Rabadi [368] evaluated the effect of providing ONS to stroke patients identi ﬁ ed as malnourished or at risk of malnutrition on mortality, dietary intake, body weight, functional status, length of hospital stay and the proportion of patients discharged home. Gariballa [367] in a small trial (20 patients per arm) explored the effect of ONS (400 ml/d, 1.5 kcal/ml and $^\texttt{5g}$ protein $/100\;\mathrm{\:ml.}$ in addition to normal hospital diet, compared to normal hospital diet alone for 4 weeks. Signi ﬁ cant differences were found at 12 weeks only for energy and protein intake, serum iron and albumin, with no differences in any other outcomes (e.g. Barthel-Index, infectious complications, length of stay and mortality). Rabadi [368] , in a trial including 58 stroke rehabilitation patients per arm, compared the effect of a highenergy high-protein ONS $(2\ \mathrm{kcal/mol}$ , 9 g protein/100 ml) with a standard energy and protein ONS $(1\,\mathrm{kcal/mol}$ , $4\,\mathrm{g}$ protein/100 ml) on length of hospital stay, functional outcomes, timed walking test and body weight. The group on high-energy high-protein ONS showed better outcome measures as functional independence measure motor score and 6-min walking test, but not in functional independence measures cognition score, length of hospital stay or body weight.

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The largest trial (FOOD trial, Food or Ordinary Diet after Stroke) [369] included 4023 patients and evaluated the effects of routine provision of ONS $(360~\mathrm{ml/d}$ , 1.5 kcal/ml, 6 g protein $'100~\mathrm{{ml})}$ in addition to hospital normal diet (irrespective of nutritional status) with normal diet alone on hospital length of stay, mortality, poor outcome (death or dependency), in-hospital complications, discharge destination, quality of life and adverse events. In this trial, there were no statistically signi ﬁ cant differences between the groups in any of the outcomes measured. However, there were several limitations in the study design that might explain this lack of effect. The most important was that nutritional assessment was not standardized, and then it was dif ﬁ cult to assess the in ﬂ uence of a nutritional intervention on nutritional status. The second limitation was the lack of monitoring of energy intake during the intervention period or at follow-up, and then it was dif ﬁ cult to assess whether the intervention group achieved a higher nutritional intake than the control group.

As mentioned above (question 33) Ha et al. [364] evaluated the effect of an individualized nutrition treatment plan including ONS or enteral feeding as required, compared with usual care in acute stroke patients aged $>65$ years identi ﬁ ed as malnourished or at risk of malnutrition (MUST) on energy and protein intake, body weight, quality of life, handgrip strength and length of hospital stay. The intervention group showed higher energy intake, prevention of weight loss, improved quality of life and handgrip strength at 3 months, but no signi ﬁ cant differences were found on protein intake and length of stay. Unfortunately, in this study the effect of ONS or tube feeding could not be differentiated. Recently, the group has published a survival study after 5 e 7 years of follow-up [366] , and no differences were found in survival between the control and the intervention group, with the exception of the subgroup of patients who had baseline plasma total carotenoids above median levels, that increased all-cause mortality. See supplementary data for Clinical Question 34 .

6.5. Clinical Question 35: Does offering texture modi ﬁ ed food compared to standard nutrition lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with dysphagia?

Recommendation 58:

Texture modi ﬁ ed diets and thickened liquids may reduce the incidence of aspiration pneumonia in stroke patients with dysphagia. Data on the effect of modi ﬁ ed diets and thickened liquids on mortality of stroke patients is insuf ﬁ cient.

Texture modi ﬁ ed diets and thickened liquids should be ordered only following an assessment of swallowing function including assessment of the risk of aspiration according to a standardized protocol (clinical and, if feasible, instrumental) by professionals trained and experienced in the assessment and treatment of dysphagia. This assessment should be repeated at regular intervals until normal swallowing function is regained.

Grade of recommendation: GPP e strong consensus $\mathbf{\{95\%}}$ agreement)

Recommendation 59:

Every stroke patient who receives texture modi ﬁ ed diets or thickened ﬂ uids should be referred for specialist nutritional assessment and counseling. This assessment should be repeated at regular intervals at least for as long as texture modi ﬁ cation and/or thickened ﬂ uids are continued.

Grade of recommendation: GPP e strong consensus $\mathbf{\{95\%}}$ agreement)

Recommendation 60:

Texture modi ﬁ ed diets and thickened liquids may lead to reduced energy and ﬂ uid intake. Every stroke patient who receives texture modi ﬁ ed diets or thickened ﬂ uids should have both ﬂ uid balance and nutritional intake monitored by trained professionals. Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 61:

In stroke patients diagnosed with thin liquid aspiration free access to water in addition to thickened liquids may be an option to thickened liquids alone.

Stroke patients diagnosed with risk of thin liquid aspiration may be allowed unthickened water in addition to thin liquids on an individual decision with regular follow-up.

Grade of recommendation: GPP e strong consensus $\mathbf{\{95\%}}$ agreement)

Recommendation 62:

Carbonated liquids may reduce pharyngeal residue when compared to thickened liquids. The use of carbonated liquids may be an option for stroke patients diagnosed with pharyngeal residue.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Commentary:

Texture modi ﬁ ed food and thickened liquids are usually used in patients with dysphagia to reduce the risk of choking and aspiration. Foods are chopped, mashed or pur eed to compensate for chewing dif ﬁ culties or fatigue, improve swallowing safety and avoid asphyxiation. Liquids are typically thickened to slow their speed of transit through the oral and pharyngeal phases of swallowing, to avoid aspiration of material into the airway and improve transit to the esophagus. Although these interventions are well established and frequently used in clinical practice, randomized controlled trials with texture modi ﬁ ed food and thickened liquids are rare. In clinical practice ﬂ uids are thickened using subjective judgement. Most studies combined interventions with texture modi ﬁ ed food and thickened liquids making it dif ﬁ cult to separate which of the two combined interventions was the one which was effective. The names, the number of levels of modi ﬁ cation and characteristics of texture modi ﬁ cation, e.g. “ thin ” , “ nectar-like ” , ” honey-like ” , “ spoon-thick ” , “ pudding ” vary within and across countries [370] . Due to this lack of an international terminology for texture modi ﬁ ed foods and thickened liquids, it is not possible to compare clinical trials with this intervention. Furthermore, it is dif ﬁ cult to transfer results from studies where the interventiontexture modi ﬁ cation-is not standardized. A great contribution to oral ﬂ uid intake is from food [371] .

A systematic review of randomized controlled trials [372] on dysphagia treatment post stroke identi ﬁ ed and reviewed the following 4 trials with interventions based on dietary modi ﬁ cations. In a RCT including 56 patients with pseudobulbar dysphagia, the effect of bolus manipulation on the recurrence of aspiration pneumonia was studied. Group I patients received a “ pureed diet ” with thin liquids, whereas those in group II received a “ soft mechanical diet ” with thickened liquids. Members of group II experienced signi ﬁ cantly fewer incidences of aspiration pneumonia during a 6-month period [373] .

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

A small randomized-controlled prospective trial included 20 stroke patients with previously identi ﬁ ed thin liquid aspiration. The control group (10 patients) received thickened liquids only. The study group (10 patients) had all liquids thickened in the same manner, but were allowed free access to water between meals in addition to the thickened liquids. No patient in either group developed pneumonia, dehydration, or complications during the course of the study, or during 30-day follow-up period. Control group subjects (thickened liquids only) averaged a mean of 27.2 days in the study (range 8 e 64 days) prior to reaching the end point of no thin liquid aspiration as documented by follow-up videoﬂ uoroscopic evaluation. Control group subjects had a mean intake of 1210 cc/day (range 400 to 1800 cc/day) of thickened liquids. Study group subjects averaged 32.9 days from onset of stroke to end point of no thin liquid aspiration, with a mean of 19.1 days in the study (range 7 e 35 days) prior to reaching the end point of no thin liquid aspiration as documented by follow-up video ﬂ uoroscopic evaluation. The mean water intake was of 855 cc/day (range 200 e 800 cc/day). It has to be stressed that patients in the study group had only additional access to water-not to other liquids like juice which pose an additional risk if aspirated due to the content of acid. Furthermore, the compliance was not assessed. In clinical practice many patients who are ordered thickened liquids take additional ﬂ uids without thickener [374] .

In one study included in the systematic review of Foley et al. [372] , both groups received thickened ﬂ uids. This means the study did not evaluate the effect of thickened liquids compared to unthickened liquids but the effect on monitoring the ﬂ uid thickness using a viscometer. The speech and language therapist determined the optimal ﬂ uid thickness for each patient. The prescribed ﬂ uid viscosity for the intervention group was obtained using a viscometer. Patients in the control group received ﬂ uids prepared according to current practice, i.e. the amount of thickener required to produce the prescribed viscosity was judged subjectively by the nursing staff. Ten patients in the study group $(\mathsf{n}=23)$ ) and nine in the control group $(\mathsf{n}=23)$ ) aspirated. The mean viscosity of ﬂ uids offered to patients in the control group was signi ﬁ cantly higher than that of the study patients. There was a statistically signi ﬁ cant correlation between the viscosity and the residual volume of ﬂ uid (Pearson's test: $\mathrm{\bf~r}=0.7,$ p < 0.02). The ﬁ ndings of the study suggest that ﬂ uids prepared by subjectively assessing the amount of thickener required to produce a given consistency tend to have a higher viscosity than those prepared using the viscometer. However, the higher viscosity does not appear to protect against pulmonary aspiration and may lead to a reduced ﬂ uid intake [375] .

Another study included in the systematic review of Foley et al. [372] , compared starch-based powder-thickened ﬂ uids with ready prepared pre-thickened ﬂ uids in 24 patients with dysphagic acute stroke requiring thickened ﬂ uids. Patients who were not on specialist stroke units and received pre-thickened ﬂ uids drank almost $100\% $ more than those on powder-thickened ﬂ uids $\mathrm{\Delta(P=0.04)}$ ) [376] .

A RCT with patients with known thin liquid aspiration post stroke randomized stroke patients in rehabilitation facilities to receiving “ thickened liquids only ” or a “ water ” protocol. For the 14 participants in rehabilitation facilities whose data proceeded to analysis, there was no difference in the total amount of beverages consumed between the water protocol group $({\mathrm{mean}}=1103~{\mathrm{m}}]$ per day, $\mathrm{{SD}}\ =\ 215\ \mathrm{{\mol}}$ ¼ and the thickened liquids only group $({\mathrm{mean}}=1103~{\mathrm{m}}\mathrm{l}$ , ${\mathsf{S}}{\mathsf{D}}=247~{\mathsf{m}}{\mathsf{l}}$ ). Participants in the water protocol group drank on average 299 ml (SD 274) of water but offset this by drinking less of the thickened liquids. Their hydration improved over time compared with participants in the thickened liquids only group, but differences between groups were not signi ﬁ cant. Twenty

one percent of the total sample was diagnosed with dehydration, and no participants in either group were diagnosed with pneumonia. There were signi ﬁ cantly more diagnoses of urinary tract infection in the thickened liquids only group compared to the water protocol group $\left(\mathbb{\chi}\left[2\right]=5.091\right.$ , $\mathsf{p}\,{=}\,0.024.$ , but no differences between groups with regard to diagnoses of dehydration $(\chi_{\scriptscriptstyle\!\!\perp}[2]=0.884$ , ${\mathsf{p}}=0.347)$ or constipation ( c [2] ¼ 0.117, $\mathsf{p}=0.733)$ [377] .

According to a literature review, the impact of bolus modi ﬁ cation on health-related quality of life in patients with oropharyngeal dysphagia appears to be negative with increased modi ﬁ cation of food and ﬂ uids often correlating with a decreased quality of life [378] . For this reason, adequate texture modi ﬁ ed diets and thickened ﬂ uids may be supportive in selected patients with oropharyngeal dysphagia, however, may lead to decreased quality of life in others. Dietary and ﬂ uid intakes of older adults in care homes requiring a texture modi ﬁ ed diet are signi ﬁ cantly less than individuals on a standard texture diet. Residents on a texturemodi ﬁ ed diet had signi ﬁ cantly lower intakes of energy (1312 [326] kcal versus 1569 [260] kcal, $\mathrm{~P~}<\,0.024,$ , non-starch polysaccharide (6.3 [1.7] g versus 8.3 [2.7] g, $\mathrm{P}<0.02.$ ) and ﬂ uid (1196 [288] ml versus 1611 [362] ml, $\mathrm{~P~}<\,0.002)$ when compared with residents on a standard texture diet [379] .

In a study observing the intake of people eating normal diet compared to people eating texture modi ﬁ ed food, the texture modi ﬁ ed group had signi ﬁ cantly lower intakes of energy (3877 versus 6115 kJ/day, $\mathrm{~P~}<\ 0.0001$ ) and protein (40 versus 60 g/day, $\mathrm{P}\,{<}\,0.003,$ ) compared to consumption of the normal diet. The energy and protein de ﬁ cit from estimated requirements over 24 h was signi ﬁ cantly greater in the texture modi ﬁ ed group (2549 versus 357 kJ, $\mathrm{P}<0.0001$ ; 6 versus 22 g, $\mathrm{P}=0.013$ ; respectively) [380] .

In a study including thirty-nine patients with a new diagnosis of ischemic stroke patients were assigned to one of two groups based on the consistency of liquids. Group 1 $(\mathsf{n}=21\$ ), thin liquids, and group 2 $(\mathsf{n}\ =\ 18)$ received nectar or honey consistency. Fluids offered and consumed were monitored for 72 consecutive hours. Patients receiving thin liquids consumed signi ﬁ cantly more than patients receiving thickened liquids $(\mathsf{m e a n}~=~1405.45~\,\mathsf{m l}$ and $\tt S D\phi=\pm727.1$ ml vs. mean ¼ 906.58 ml and $\tt S D\;=\;\pm317.4\,\mathrm{\small~ml~}$ ; $\mathsf{p}=0.0031.$ ). However, they were also offered signi ﬁ cantly more ﬂ uids $\mathrm{{mean}=2574.7\;\mathrm{{ml}}}$ vs. 1588.9 ml, $\mathsf{p}=0.0002.$ ) [381] .

In a retrospective chart review completed on 67 ischemic stroke patients, patients on modi ﬁ ed solid diets or thickened liquids due to dysphagia showed a signi ﬁ cantly elevated BUN/Cr values at discharge [382] , as a indicator of poor hydration status.

In a small study neurologically impaired patients had to swallow liquids with the following consistencies three times: thin, thickened and carbonated. The liquids were given in doses of $3~\times~5~\mathrm{{\mil}}$ . The swallows were analyzed videoradiographically regarding penetration/aspiration, pharyngeal transit time and pharyngeal residue. Signi ﬁ cant difference was found regarding penetration/aspiration when comparisons were made between thin liquid and carbonated thin liquid $\mathbf{\dot{p}}<0.0001\mathbf{\dot{\bar{\rho}}}$ ). The comparison between thin liquid and thickened liquid $\mathbf{\dot{p}}<\mathbf{0}.0001$ ) showed signi ﬁ cant less penetration with thickened liquids. Pharyngeal residue was signi ﬁ cantly reduced $\mathsf{\tilde{p}}<0.0001)$ with carbonated thin liquid compared to thickened liquid. Pharyngeal transit time was reduced both when comparing thin liquid with thin carbonated liquid $\mathbf{\dot{p}}<0.0001$ ) and thickened liquid $\mathbf{\dot{p}}<0.0001$ ). However, this study did only look at swallowing during a videoradiographic analysis, not on swallowing outside laboratory conditions and did not investigate clinical endpoints like aspiration pneumonia [383] .

In summary, currently there is a lack of evidence on the positive as well as on the adverse effects of texture modi ﬁ ed diets in stroke patients with dysphagia. Many trials with texture modi ﬁ ed food

and thickened liquids as an intervention do not focus especially on stroke patients. See supplementary data for Clinical Question 35 .

6.6. Clinical Question 36: Does tube feeding compared to other feeding strategies lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with severe dysphagia?

Recommendation 63:

Patients with prolonged severe dysphagia after stroke that presumably last for more than 7 days should receive early (not more than 72 h) enteral tube feeding.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Recommendation 64:

Critically ill stroke patients with decreased level of consciousness that need mechanical ventilation should receive early (not more than 72 h) enteral tube feeding.

Grade of recommendation: B e strong consensus $\bf{(100\%)}$

Commentary:

Around $8.5{-}29\%$ of stroke patients require tube feeding in the acute phase of stroke [384] . However, it remains unclear what kind of stroke patients can improve their prognosis with enteral feeding [19 e 21] . Probably, previously malnourished patients could bene ﬁ t the more, although this af ﬁ rmation has not been proved. In the FOOD trial-2 [385] , early enteral feeding (within seven days after stroke) was compared with tube feeding initiated after seven days in 859 patients. Early tube feeding reduced mortality in dysphagic patients by $5.8\%$ , compared with the group of “ late ” initiation, although the differences were not signi ﬁ cant. However, the proportion of patients surviving with poor outcome (great disabilities) was higher in the group who started early enteral nutrition, as well as prevalence of gastrointestinal bleeding. It could be speculated that these patients with poor outcome probably would not have survived without enteral nutrition. This study suffers from important limitations in the design. The ﬁ rst is the lack of standardization of nutritional assessment (as previously stated), but probably the most important bias for this question is that patients with a clear indication for early tube feeding were not included, only those in which the attending physician was unsure about the adequate nutritional therapy. Zheng [386] evaluated the impact of early enteral nutrition (within 72 h of admission) on short term prognosis after acute stroke. However, this non-randomized study has serious limitations in the design, as they compared 75 patients admitted to a stroke unit managed with enteral nutrition with 71 patients admitted to the regular ward that received familymanaged oral nutrition.

Critically ill stroke patients with a severe decreased level of consciousness that need mechanical ventilation can bene ﬁ t from enteral nutrition. In ESPEN Guidelines on enteral nutrition: Intensive care [387] , critically ill patients bene ﬁ t from early medical nutrition therapy (preferably by the enteral route) if they cannot meet their nutritional requirements by the oral route within three days. Although the studies that support this recommendation are not performed speci ﬁ cally in stroke patients, the bene ﬁ cial effects may be extrapolated to stroke patients.

Patients with presumably long duration of dysphagia (more than 7 days) because of the severity of stroke or certain cerebral infarct localizations (as bulbar and brainstem areas) are at nutritional risk and therefore they can bene ﬁ t from enteral nutrition. In these cases, enteral nutrition should start early, as acquired

malnutrition is a negative prognostic factor for outcome in stroke patients [333,388,389] . See supplementary data for Clinical Question 36 .

6.7. Clinical Question 37: Does tube feeding via PEG compared to nasogastric tube feeding lead to lower morbidity and mortality or improve other outcomes in acute stroke patients with dysphagia?

Recommendation 65:

If a suf ﬁ cient oral food intake is not possible during the acute phase of stroke, enteral nutrition should be preferably given via a nasogastric tube.

Grade of recommendation: A e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 66:

If enteral feeding is likely necessary for a longer period of time $\scriptstyle(>\!28$ days), a PEG should be chosen and placed in a stable clinical phase (after 14 e 28 days).

Grade of recommendation: A e strong consensus (95% agreement)

Recommendation 67:

In a subgroup analysis of patients with dysphagia needing PEG placement, the “ pull ” technique was superior and then should be preferred when compared with the “ push ” technique. Grade of recommendation: B e strong consensus (100% agreement)

Recommendation 68:

Stroke patients mechanically ventilated for longer than 48 h may receive a PEG at an early stage (usually within 1 week).

Grade of recommendation: 0 e consensus ( $\mathbf{\{85\%}}$ agreement)

Recommendation 69:

If a nasogastric tube is repeatedly removed accidentally by the patient and if enteral nutrition will probably be necessary for more than 14 days, a nasal loop/bridle may be applied to secure the nasogastric tube.

Grade of recommendation: B e strong consensus (95% agreement)

Recommendation 70:

If a nasogastric tube is rejected or not tolerated (after several attempts) by the patient and if medical nutrition will probably be necessary for more than 14 days and the application of a nasal bridle is not feasible or not tolerated, early feeding via PEG should be started.

Grade of recommendation: GPP e strong consensus $\mathbf{(93\%}$ agreement)

Recommendation 71:

Nasogastric tube feeding does not worsen dysphagia and is therefore no obstacle to dysphagia rehabilitation. Dysphagia therapy should therefore start as early as possible in all stroke patients. Grade of recommendation: B e strong consensus $\mathbf{\{90\%}}$ agreement)

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Recommendation 72:

If there are symptoms of unexplained worsening of dysphagia in patients fed via nasogastric tube, the pharyngeal tube position should be controlled endoscopically.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\left.90\%\right.}$ agreement)

Commentary:

Between 23 and $78\%$ of all stroke patients suffer from relevant dysphagia, dependent on the diagnostic technique [4,390] . Frequently, this leads to aspiration within the ﬁ rst days after stroke. The majority of patients have “ silent ” aspiration [391] . Severity of stroke, aphasia, as well as dysphasia, and lesions of the frontal and insular cortex as well as the brain stem are predictors for prolonged dysphagia $^{\prime}{>}14$ days) [4,384] . Between $8.5\%$ and $29\%$ of stroke patients require tube feeding in the acute phase of stroke [392] .

Dysphagia due to ischemic stroke resolves within 7 e 14 days in $73{-}86\%$ of the cases [393 e 395] . It is therefore worthwhile to consider an access to enteral nutrition which is less invasive than PEG at ﬁ rst. At present, only two prospective, randomized, controlled intervention studies had been comparing nasogastric tube feeding and PEG feeding after stroke.

In a recent Cochrane review, feeding of adults with swallowing disturbances via PEG tube versus feeding via nasogastric tube were compared [396] . However, the population included adults with swallowing dif ﬁ culties of various etiologies, i.e. also patients with dysphagia caused by other diseases than by stroke were included. Intervention failure occurred in lower proportion of participants with PEG compared to nasogastric tubes. There was no statistically signi ﬁ cant difference of the secondary outcomes mortality, overall reports of adverse events at any follow up time point, speci ﬁ c adverse events including pneumonia and nutritional status. However, there was evidence in favor of PEG of mid-arm circumference change from baseline and levels of serum albumin were higher in the PEG group. Quality of life was measured in two studies with 133 participants. The intervention favored PEG: Fewer participants found the application of a PEG to be inconvenient, uncomfortable or interfering with social activities. The studies were subgrouped by endoscopic technique into pull, push and “ not reported ” . There was a signi ﬁ cant difference favoring the “ pull ” subgroup. The most widely used method of PEG placement is the “ pull ” method or standard Ponsky technique. The “ push ” modi ﬁ cation of this procedure, based on the Russell introducer technique, avoids transoral passage of the PEG by direct insertion through the abdominal wall over a guidewire under endoscopic guidance. As this Cochrane review did not speci ﬁ cally address stroke patients with dysphagia, we analyzed studies especially addressing this patient group.

In a Cochrane review on “ Interventions for dysphagia and medical nutrition therapy in acute and subacute stroke ” [21] the authors conclude that, compared with nasogastric feeding, PEG reduced treatment failures and gastrointestinal bleeding and had higher feed delivery. Albumin concentrations were higher in the PEG group. The study published by Norton et al. [397] included 30 stroke patients. 16 patients were assigned to the PEG-group. They had a better nutritional status, lower mortality and shorter hospital stay after 6 weeks of intervention. However, it has to be taken into account that the study population consisted of severely impaired elderly stroke patients, with an average age of 79 years. All patients were unconscious on admission, had hemiplegia and their BarthelIndex (Katz Index for Activities of Daily Living, ADLs) was only three points on average (on a scale from 0 to 20 points).

The only randomized, controlled study evaluating timing of feeding in stroke patients, was the “ Early versus Avoid Trial ” of the

FOOD-study, which was published in 2005 [369,398] . It was also the study with the biggest sample size (859 patients) addressing this question. After randomization tube feeding was either started as soon as possible or the placement of the tube was delayed for at least seven days. During this period, ﬂ uid was given intravenously or subcutaneously. Whether enteral nutrition was given via a PEGtube or a nasogastric tube, was decided by the attending physician. In 429 patients, a nasogastric tube was chosen; only 10 patients received a PEG-tube. The group of patients that started enteral nutrition within 7 days of admission had a reduction in mortality by $5.8\%$ , which was not signi ﬁ cant. The proportion of patients surviving with poor outcome was greater in the group with early nutrition (de ﬁ ned as Rankin Score 4 or 5). It could be speculated that these patients with an “ impaired outcome ” would have died with a delayed start of nutrition. Pneumonia did not occur more often in patients that received early enteral nutrition. Gastrointestinal bleeding occurred more often in early feeding than in delayed feeding. In this study, patients were only included when the attending physician was not sure about the timing of feeding. Nutritional status was not evaluated by standardized screening, but recorded informally by the attending physician. Together with some other limitations of the study, the amount of tube feed given was not documented.

It is recommended to start early enteral nutrition in patients, who are anticipated to have swallowing dif ﬁ culties for more than seven days and therefore not reach a suf ﬁ cient oral intake. The FOOD-trial showed no differences between PEG feeding and nasogastric tube feeding regarding the endpoint “ death after six months ” in 321 dysphagic stroke patients [369,398] . The mean age of the study population was 76 years. At admission $16\%$ of patients could raise both arms, $3\%$ could walk without help and $25\%$ had a normal verbal Glasgow Coma Scale. After six months patients with nasogastric tube showed a signi ﬁ cantly $(7.8\%)$ lower risk of the combined end point “ death and/or impaired functional status ” when compared to patients with early PEG feeding. A limiting factor of the study was that only patients, in whom the attending physician was “ not sure ” about the best nutritional therapy (which means nasogastric or PEG tube), were included. Unfortunately, this study does not give information about the number of patients per center that were not included in the study and the reasons for exclusion. Furthermore, tube placement occurred considerably later in patients, who were randomized to the PEG-group than in patients in the nasogastric-group. Eighty percent of the patients with the nasogastric tube received tube on the ﬁ rst day after randomization. In the PEG-group only $70\%$ of PEG-tubes were placed within 4 days, $80\%$ were placed within 14 days after insult. In this study, most patients were recruited in British hospitals, where, at the time of the study, it took several days to get an appointment for PEG-tube placement. The fact that intervention was not possible directly after randomization, limits the comparability between the two study groups. The effects of a delayed nutrition therapy are known from other studies, amongst others from the “ Avoid versus Early-tube ” -part of the FOOD-trial. There was an increased prevalence of pressure sores in the PEG-group. Two possible explanations of the difference can be discussed: On the one hand patients with a PEG-tube might have been less mobile, due to the tube placed in the abdominal region and therefore suffered from an increased rate of pressure sores. On the other hand, it is conceivable, that patients with a PEG were attended differently (e.g. less intensively) by the nursing staff than those with a nasogastric tube. In case of the latter theory, the worse functional result of the PEG-group would not have been directly caused by the enteral access and nutrition, but by the different treatment and care of the patients. Taking into account the inclusion criteria, the results of the FOOD-trial have to be treated with

caution when applied to the overall group of dysphagic stroke patients.

In another small prospective randomized study published by Park et al. [399] , a group of 40 patients with persisting neurological dysphagia ' 18 were stroke patients, the patients fed via PEG tube had a better nutritional status compared to the group fed via nasogastric tube. On day twenty-eight 18 out of 19 patients in the nasogastric tube e group had ful ﬁ lled the criteria for a “ treatment failure ” : hereupon feeding was changed to PEG-tube. Outcome could not be evaluated due to the small number of patients left in the nasogastric group. This is showing the common practical problems with a nasogastric tube, like non-tolerance of the nasogastric tube.

In general, dislodgement of nasogastric tubes causing poor enteral nutrition is a common problem in daily routine. Two studies about nasal loops in stroke patients demonstrated that nasal loops are safe, well tolerated and effective at delivering full enteral nutrition [400] . A randomized controlled trial observed an increase of $17\%$ mean volume of ﬂ uid and tube feed given in the nasal loop group. The intervention period was limited to 2 weeks. The nasal loop ameliorated electrolyte disturbances and reduced nasogastric tube failure. However, no differences were seen in terms of mortality, morbidity, PEG placement, functional outcomes and length of hospital stay at 3 months follow up [401] . The long term outcome in this patient group was poor: 88/104 (84%) were either dead or severely disabled at 3 months follow up. There is insuf ﬁ cient evidence to support a recommendation of mittens. In centers where they are used, a locally agreed protocol should be in place to minimize the risk of associated complications [20] .

A randomized study published by Kostadima et al. [402] reported that early nutrition (within 24 h) via PEG in 41 mechanically ventilated patients with stroke or head injury was superior to feeding via nasogastric tube, and it was associated with a lower prevalence of ventilator-associated pneumonia. However, a signi ﬁ cant difference in length of stay and mortality could not be found. Conclusions for the treatment of ventilated stroke patients can be drawn from this study, as stroke patients were represented with $61\%$ . In particular, in mechanically ventilated stroke patients, in whom prolonged arti ﬁ - cial nutrition $^{\circ}\!>\!14$ days) is probable, early feeding via PEG (usually within 1 week) should be preferred to nasogastric tube feeding, due to a lower rate of ventilation related pneumonia [402,403] .

Particularly in stroke patients with unfavorable prognosis, ethical considerations and living-will decisions should be specially considered. In doubt, a semi-invasive nutrition with nasogastric tube feeding might be more appropriate as a ﬁ rst step. The indication for arti ﬁ cial nutrition should be reconsidered daily and in particular thoroughly reassessed before transfer to a nursing home or a palliative-care unit. Tube feeding may be ﬁ nished, if the medical indication no longer exists, most likely in a palliative situation. In patients with an uncertain prognosis, PEG-insertion should not be a criterion for the admittance to a rehabilitation ward or to a nursing home, especially if a nasogastric tube is well tolerated.

Due to the risk of internal pressure sores, small diameter nasogastric feeding tubes (8 French) should be used in stroke patients. Tubes with a greater diameter should only be placed if gastric decompression is necessary. The placement of a nasogastric tube should be done by trained and technically experienced medical staff. Due to the risk of misplacement, the correct position should be controlled before the application of tube feed. This can be done via x-ray or by the aspiration of gastric content. A further possibility to control tube position is the measurement of gastric pH [404] . A local standard for the assessment of correct tube placement should be developed in every hospital.

In a group of patients with miscellaneous diseases swallowing dif ﬁ culties were observed in $17.4\%$ of patients with nasogastric tube feeding, compared to none in the PEG group [405] . In addition to

another study, which observed alterations of swallowing in healthy volunteers [406] , these results partly led to the assumption that therapy for dysphagia might not be possible with a nasogastric tube in situ. This assumption is contradicted by three recent studies, with two of them in stroke patients, that did not observe a negative impact of nasogastric tube feeding on swallowing function [407 e 409] . Dysphagia therapy should therefore start as early as possible, in tube-fed as well as non-tube-fed patients. Dziewas et al. demonstrated that in most cases of worsening of dysphagia with a nasogastric tube, this was due to misplacement with coiling of the tube in the pharynx [409] . A reinsertion of the tube or even more favorable an endoscopic evaluation of the pharyngeal tube position is therefore recommended in this situation.

7. Oropharyngeal dysphagia. Additional aspects

7.1. Clinical Question 38: What is the role of food texture and liquid viscosity modi ﬁ cation in the treatment of oropharyngeal dysphagia?

Recommendation 73:

There is strong evidence that the risk of aspiration can be reduced in adults with oropharyngeal dysphagia of different etiologies by increasing liquid viscosity. However, thickened liquids may increase the risk of post-swallow oral and pharyngeal residues.

Texture modi ﬁ ed diets and/or thickened liquids should be prescribed only after a clinical swallow exam and/or instrumental dysphagia assessment (VFSS or FEES) has been carried out.

Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 74:

There is evidence that using thickened liquids fails to substantially increase ﬂ uid intake in persons with OD. Liquid thickening should be applied in patients with OD aspirating on liquids, however, liquid intake needs to be closely monitored since there is a high risk of insuf ﬁ cient oral intake.

Grade of recommendation: A e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 75:

To improve patients' compliance different types of thickening agents should be offered for choice.

Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 76:

Modi ﬁ ed textures and thickened liquids should be used in persons with chronic dysphagia to enhance nutritional status.

Grade of recommendation: B e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 77:

In spite of applying food texture and liquid viscosity modiﬁ cations patients with OD are at an increased risk of malnutrition, dehydration and aspiration pneumonia and, hence, should be carefully monitored for these complications.

Grade of recommendation: GPP e strong consensus $\mathbf{\{95\%}}$ agreement)

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Commentary:

The use of texture-modi ﬁ ed foods and thickened liquids has become a cornerstone of clinical practice to address OD. The principle behind this approach arises from the assumption that modifying the properties of normal foods and liquids will make them safer and easier to swallow [410] . In spite of the pervasive use of texture modi ﬁ cations as clinical intervention, the speci ﬁ c scienti ﬁ c foundation, although convincing in some aspects, is with regards to some important issues still incomplete or inconclusive.

For decades there were no established and universally used terminology and de ﬁ nitions to describe the target consistency recommended for patients with OD and to guide its preparation [410] . Several countries have developed their own taxonomies or classi ﬁ cation systems [410,411] . Only recently the “ International Dysphagia Diet Standardization Initiative ” (IDDSI) has been established that pursues the goal to develop global standardized terminology and de ﬁ nitions for texture modi ﬁ ed food and thickened liquids for individuals of all ages, in all care settings, and all cultures [412] . In general, an inconsistent approach in de ﬁ ning and measuring rheological properties of food and liquid items limits the comparability of studies performed and the validity of conclusions reached in this area. There is a strong need for establishing internationally accepted and uniformly used standards of measuring and grading rheological characteristics of bolus textures.

In spite of these problems with regards to terminology, the effect of liquid thickening on the physiology of impaired swallow responses has been thoroughly investigated. There are two recent systematic reviews [410,412] and one white paper [413] summarizing the evidence of more than thirty studies devoted to this topic. The concordant conclusion of these three high-quality papers is that liquid thickening reduces the risk of airway penetration and aspiration in different patient populations suffering from OD. Although the available data are insuf ﬁ cient to suggest particular viscosity values, the analysis put forward by Newman and colleagues suggest that on the continuum covering the whole spectrum from “ thin ” , “ nectar ” , “ honey ” to “ spoon thick ” there seems to be a dose e response characteristic with thicker liquids being safer than thinner liquids [413] . On the other side of the same medal, liquid thickening seems to increase the risk of post-swallow residues [410,412,413] . Although not as unequivocal and as frequently studied as aspiration, several studies reported oral and/or pharyngeal residues with ultra-thick liquids [79,414 e 416] .

Apart from these physiological effects, clinically relevant endpoints have also been studied in the context of liquid thickening and texture modi ﬁ cations. Contrasting with its positive effect on swallowing safety liquid thickening has failed to substantially improve ﬂ uid intake in several studies [375,376,417,418] and systematic reviews [202,419,420] with aversion for this type of diet being probably among the main reasons for this ﬁ nding [421] . Thus, thickeners are suggested to suppress ﬂ avor, induce a “ coating feeling ” in the mouth and do not reduce the physiological sensation of thirst [422] . As a consequence of all these aspects, the use of thickeners has been associated with a decreased quality of life in a recent systematic review [378] . Interestingly, differences in the palatability of different thickeners, in particular starch-versus gumbased thickeners, have been identi ﬁ ed at the individual level and with regards to the thickened beverages [423,424] .

Apart from the viscosity, type of thickeners also impact on other characteristics of the liquids like texture, taste and appearance. There is evidence that the different types of thickening agents available differ in this respect, leading to differences in palatability and, potentially, in patients compliance.

The impact of feeding strategies involving texture modi ﬁ ed diets on oral intake has been assessed in one small RCT [425] . In elderly dysphagic nursing home residents, both dietary intake and nutritional status signi ﬁ cantly increased in the intervention group over a time period of 12 weeks. In addition, a cohort study in acute stroke patients showed that by being given a dysphagia diet patients could achieve more than $75\%$ of their energy requirements [426] .

The effect of dietary interventions in the prevention of aspiration pneumonia has been evaluated in several systematic reviews related to nursing home residents with dementia [427] , elderly persons with stroke [372] and elderly persons with OD of heterogeneous etiologies [202,419,420] . It is generally concluded that the number of high quality studies is too low to recommend the use of texture modi ﬁ ed food and thickened liquids for the prevention of aspiration pneumonia. In particular, Robbins et al. in their large RCT recruiting over 500 patients with OD due to Parkinson's disease or dementia and proven aspiration on thin liquids, did not ﬁ nd a signi ﬁ cant difference in the incidence of aspiration pneumonia between the group receiving thickened liquids and the group being treated with chin-down posture and normal liquids [227] .

7.2. Clinical Question 39: Which exercises and maneuvers to rehabilitate oropharyngeal dysphagia are available?

Recommendation 78:

Prior to initiating a behavioral swallowing therapy patients should be assessed by a clinical swallowing exam or, preferentially, by an instrumental testing (VFSS, FEES). During the further course treatment effects should be reevaluated on a regular basis.

Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 79:

There is strong evidence that the Shaker head lift, a combination of an isometric and an isokinetic exercise, has favorable long-term effects by improving the strength of the suprahyoid muscles over time, and increasing the opening of the upper esophageal sphincter. We recommend the Shaker head lift for the treatment of upper esophageal sphincter dysfunction.

Grade of recommendation: A e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 80:

There is evidence that expiratory muscle strength training (EMST training) improves swallowing dysfunction in OD of different etiologies.

EMST is recommended in patients with motor-neuron disorders and Parkinson's disease. EMST treatment should preferentially be applied within RCT.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 81:

The chin-down maneuver is recommended in patients with premature spillage and predeglutitive aspiration.

Grade of recommendation: B e strong consensus (94% agreement)

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Recommendation 82:

Systematic and suf ﬁ ciently frequent swallowing therapy making individualized use of the different exercises available is recommended in patients suffering from OD.

Grade of recommendation: B e strong consensus ( $\bf{100\%}$ agreement)

Commentary:

Exercises and maneuvers probably constitute the most widespread treatment approach for patients with OD worldwide. A variety of different interventions exist, ranging from direct to indirect, isolated to combined and those incorporating swallowing and nonswallowing tasks. Rehabilitation exercises are intended to change and improve the swallowing physiology in force, speed or timing and are meant to produce long-term effects. In contrast to this, compensatory interventions are used for short-term effects on the swallow [428] . Contrasting with its wide-spread application, the scienti ﬁ c evidence for the ef ﬁ cacy of this type of treatment is heterogeneous with a general lack of large RCTs providing clinical meaningful endpoints [202,429] .

The Shaker head lift is one of the best studied exercises used in dysphagia rehabilitation for many years and is designed for patients with weakness of the suprahyoid muscles and impaired opening of the upper esophageal sphincter [430] . This procedure is a head rising exercise with an isometric high-intensity portion with three head lifts held for 60 s with a 60 s rest period between each one and an isokinetic low-intensity portion that included 30 consecutive head lifts of constant velocity without holding. The Shaker head lift has been evaluated in systematic reviews [202,431] and several RCT [432 e 436] showing that this treatment improves strengths and endurance of the suprahyoid muscles and upper esophageal sphincter opening. In addition, there is evidence that residues and aspiration events are reduced.

The chin-down is a technique used for patients who have decreased airway protection associated with delayed swallow initiation and/or reduced tongue base retraction. Patients are instructed to “ bring their chin to their chest ” and maintain this posture throughout the duration of the swallow [430] . In several studies, physiological changes like expansion of the vallecular recesses, approximation of the tongue base toward the pharyngeal wall, narrowing of the entrance to the laryngeal vestibule, expedited onset of laryngeal vestibule closure, reduction in distance between hyoid and larynx, and increased duration of swallowing apnea [430,437,438] . In two well-designed cohort studies of patients with OD presenting with aspiration, the aspiration risk could be reduced by approximately $50\%$ [439,440] .

Among the muscles that can be targeted by exercise are also those of the tongue, which plays a major role in bolus formation, control and propulsion in swallowing. Several studies show that tongue strength declines in healthy aging [441,442] and reduced tongue strength has been identi ﬁ ed as a risk factor for aspiration [443,444] . Tongue strength training has been evaluated in OD in some well-done cohort studies [445 e 447] . These trials report different improvements of swallowing variables like vallecular residues and swallowing safety.

The Lee Silverman voice treatment has been designed to improve vocal intensity in PD patients. In one small cohort study of 8 PD patients the authors found several improvements in the oral and pharyngeal stage of swallowing [231] . There is insuf ﬁ cient evidence to recommend the Lee Silverman voice treatment to improve OD.

Expiratory muscle strength training (EMST) involves exhaling quickly and forcefully into a mouthpiece attached to a one-way

valve, blocking the ﬂ ow of the air until the patient produces suf ﬁ - cient expiratory pressure. It is meant to strengthen the expiratory and submental muscles by increasing the physiologic load [428] . This treatment has shown signi ﬁ cant effects on swallowing safety in a RCT in Parkinson patients [229] , has improved swallowing safety and feeding status in a RCT in subacute stroke patients [448] , has been associated with positive effect on swallowing-related muscle strength in elderly participants [449] , and has been found to improve swallow kinematics, in particular hyoid displacement, in a cohort study with pre-post design in ALS patients [450] . No effect on swallowing parameters and related outcomes were observed in patients with Huntington's disease [451] .

The effortful swallow is used for patients who present with clinically signi ﬁ cant residue in the valleculae and/or pyriform sinuses as well as for patients who may have decreased airway closure [430] . Physiologically, the effortful swallow has been shown to increase hyolaryngeal excursion, duration of hyoid elevation and UES opening, laryngeal closure, lingual pressures, peristaltic amplitudes in the distal esophagus and pressure and duration of tongue base retraction in healthy subjects [452 e 455] . Effects over time were studied in a RCT in healthy individuals. The main ﬁ nding was that lingual pressure increased, albeit insigni ﬁ cantly, after four weeks of exercising the effortful swallow [456] . In addition, a second small cohort study assessed the effect of this exercise in patients with Parkinson's disease and found improved pharyngeal manometric pressure after a two-week treatment period [457] .

The Masako maneuver involves swallowing while protruding the tongue beyond the lips, holding it between one's teeth. It is meant to have a strengthening effect on the tongue and the pharyngeal walls after a period of training [458] . Studies in healthy subjects did not ﬁ nd immediate effects on swallowing physiology [459,460] . A RCT including healthy subjects exposed to a four week training with the Masako maneuver or a control task found no effect on the swallow [461] . In a small RCT recruiting subacute stroke patients, the Masako maneuver was compared with neuromuscular electrical stimulation. In that trial, both groups showed improvement of swallowing function, however, since a control group was missing, these results need further con ﬁ rmation [462] .

The Mendelsohn maneuver is a technique used for patients with decreased hyolaryngeal excursion and/or decreased duration of UES opening and is frequently combined with some form of biofeedback to help the patient perform it. To execute this maneuver, patients are instructed to keep the thyroid cartilage for several seconds in an elevated position before ﬁ nishing the swallow [430] . Long-term effects of the Mendelsohn maneuver have been evaluated in one RCT in stroke patients [463,464] . In that study, the authors could demonstrate that hyoid movement and upper esophageal sphincter opening improved after treatment.

The super-supraglottic swallow is used as compensatory maneuver for patients with reduced airway closure. This maneuver involves a person holding a tight breath, swallowing while keeping the airway closed, then immediately coughing after the swallow. It has been shown in several studies that the super-supraglottic swallow has immediate effects on swallowing physiology [465 e 467] , but there are no studies investigating long-term effects of this maneuver [428] .

Re ﬂ ecting the fact that patients suffering from OD have a highly variable pattern of speci ﬁ c swallowing abnormalities, more complex treatment approaches combining different adaptive, compensatory and rehabilitative techniques have been employed in a variety of studies. In their systematic review Speyer and coworkers summarized 4 RCTs and 27 nonrandomized trials most of which showing signi ﬁ cant improvements of swallowing function and related endpoints [429] . The largest RCT to date has been performed by Carnaby et al. [468] in stroke patients. The authors

compared the change of dietary status after usual care $(\Nu=102$ ), standard low-intensity intervention $(\mathsf{N}=102)$ ) and standard highintensity intervention ${\bf N}=1021$ ). After six months, the percentage of patients returning to a normal diet was $56\%$ for usual care, $64\%$ for standard low-intensity and $70\%$ for standard high-intensity treatment. In patients who received standard therapy (either low or high intensity) medical complications, chest infections and death or institutionalization decreased signi ﬁ cantly. Recently, two systematic treatment programs have been evaluated in nonrandomized trials. The McNeill dysphagia treatment protocol improved swallowing physiology in an observational study [469] , as well as diet and clinical swallowing ability in a case e control and a cohort study [470,471] . The intensive dysphagia rehabilitation protocol was tested in a small observational study and led to an improvement of aspiration severity and level of oral intake [472] .

7.3. Clinical Question 40: Which types of neurostimulation treatment approaches are available for patients with oropharyngeal dysphagia?

Recommendation 83:

Prior to initiating any stimulation therapy targeting OD, patients should receive a clinical swallow exam or, preferentially, an instrumental swallow evaluation. This evaluation should be repeated after the treatment has been ﬁ nished.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\lambda}^{\mathbf{100\%}}$ agreement)

Recommendation 84:

Due to the limited number of evidence, all stimulation treatments should preferentially be carried out within clinical trials.

Grade of recommendation: GPP e strong consensus (95% agreement)

Recommendation 85:

There is evidence that neuromuscular electrical stimulation (NMES) improves swallowing function in patients with OD of different etiologies. NMES applied together with behavioral swallowing treatment is superior to behavioral swallowing treatment alone, in particular in post-stroke OD. NMES may be used alone, or preferentially, as adjunct to behavioral swallowing treatment in patients with OD.

Grade of recommendation: B e strong consensus ( $\bf{100\%}$ agreement)

Commentary:

Apart from traditional swallowing training and bolus modi ﬁ - cation strategies, several adjunctive treatment options have been explored recently. These treatments include surface neuromuscular electrical stimulation (NMES), pharyngeal electrical stimulation (PES), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). NMES and PES target the neuromuscular system peripherally, rTMS and tDCS focus on the central swallowing network. Although these treatment options have been applied frequently and in different patient populations, there is still a lack of large multicenter RCTs with meaningful clinical endpoints.

NMES is used to activate sensory nerves or muscles involved in swallowing function through stimulation of axonal motor nerve endings and muscle ﬁ bers. Its mechanism of action is thought to

include accelerating the development of muscle strength and promoting central nervous system recovery. This treatment that is usually applied as adjunct to behavioral swallowing therapy has been evaluated in several mostly small studies (case control and cohort studies as well as single-center RCTs) including patients with OD of different etiologies, predominantly post-stroke. So far, three meta-analyses have been performed that all point towards a modest effect of NMES both on swallowing physiology as well as on feeding status [473 e 475] . These ﬁ ndings have been corroborated in two recent RCTs not included in these meta-analyses. Park et al. showed improved hyoid-movement in subacute stroke patients being treated with NMES in combination with effortful swallowing compared to effortful swallowing alone [476] . Terre and Mearin found improved feeding status in patients with OD after stroke or traumatic brain injury when being exposed to NMES and conventional swallowing therapy compared to conventional swallowing therapy alone [477] .

Non-invasive brain stimulation is based on the principle of neuroplasticity, best de ﬁ ned as changes in neuronal pathways to increase neural functioning via synaptogenesis, reorganization, and network strengthening and suppression. The two most commonly used techniques to directly target cortical areas are tDCS and rTMS, whereas PES applies stimulation to pharyngeal structures, indirectly targeting the pharyngeal motor and sensory cortices and related brain areas. Both tDCS and rTMS have been evaluated in several small RCTs and cohort studies, most of them focusing on patients with OD due to acute or chronic stroke. Three metaanalyses have been performed, each with a slightly different subselection of studies [478 e 480] . Concordant conclusion of all three studies was that noninvasive brain stimulation was associated with sustained improvement of swallowing function compared to sham treatment. PES has successfully been used in three RCTs recruiting dysphagic stroke patients and one RCT devoted to patients with multiple sclerosis suffering from OD [481 e 483] . Apart from that, a meta-analysis con ﬁ rmed a positive treatment effect of PES [484] . However, in a large multicenter RCT of subacute dysphagic stroke patients, PES did not improve dysphagia when compared to sham treatment [485] .

7.4. Clinical Question 41: Which pharmacological treatments are available for patients with oropharyngeal dysphagia?

Recommendation 86:

Prior to considering a pharmacological treatment in a patient with OD, a clinical swallow exam or, preferentially, an instrumental swallow evaluation should be carried out.

Grade of recommendation: GPP e strong consensus ( $\mathbf{\cdot100\%}$ agreement)

Recommendation 87:

Pharmacological treatment options, in particular TRPV1 agonists and dopaminergic agents, may be used as adjunct to behavioral swallow therapy in patients, in whom a delayed swallow re ﬂ ex had been identi ﬁ ed as main feature of OD.

Grade of recommendation: B e strong consensus $\mathbf{\cdot100\%}$ agreement)

Recommendation 88:

Due to the limited evidence with regards to clinical endpoints, pharmacological treatment decisions need to be individualized and have to be based on a careful risk-bene ﬁ t analysis.

Please cite this article in press as: Burgos R, et al., ESPEN guideline clinical nutrition in neurology, Clinical Nutrition (2017), https://doi.org/

10.1016/j.clnu.2017.09.003

Grade of recommendation: GPP e strong consensus ( $\bf{100\%}$ agreement)

Commentary:

Pharmacological treatment of OD involves the use of drugs that stimulate the neural pathways of deglutition either on the peripheral sensory level or at different levels of the central nervous system [486] . Classes of pharmacological agents that have been evaluated for their potential to improve disordered swallowing are TRPV1 (transient receptor potential cation channel subfamily V member 1) agonists, angiotensin-converting-enzyme-inhibitors and dopaminergic agents. Overall, the potential of this treatment approach has not been fully explored, and in particular suf ﬁ ciently powered multicenter RCTs with clinically relevant endpoints are required.

TRPV1 agonists, in particular capsaicinoids and piperine, stimulate TRPV1 receptors expressed at free nerve endings of the superior laryngeal nerve and the glossopharyngeal nerve [487,488] . Several observational studies, case control studies and one RCT [489 e 494] have shown that TRPV1 agonists improve the safety of the swallow by decreasing the latency of the swallow re ﬂ ex, by shortening laryngeal vestibule closure time and by enhancing hyoid motion. However, studies with clinical endpoints have not been conducted so far.

Loss of dopaminergic neurons in the central nervous system due to stroke or neurodegenerative diseases is known to contribute to OD and is in particular associated with a decreased swallow re ﬂ ex [495] . Application of levodopa has been shown to normalize the onset of the pharyngeal swallow in a RCT with cross-over design that recruited patients with post-stroke OD [496] . A second RCT focusing on a similar study population found that nocturnal aspiration episodes were reduced by treatment with either amantadine or cabergoline (dopamine receptor agonist) [497] . Finally, in the largest RCT to date, Nakagawa and co-workers showed that treatment with amantadine signi ﬁ cantly decreased the rate of pneumonia in poststroke patients over the study period of three years [498] .

ACE inhibitors are widely used antihypertensive drugs that can cause a dry cough as a side effect. One of the mechanisms for this side effect is the decreased degradation of substance P, which is released from sensory nerve terminals in the nasopharynx. Substance P in turn is known to enhance the swallow re ﬂ ex and there is evidence that decreased sputum levels of this neurotransmitter are associated with aspiration pneumonia [499] . In line with this pathophysiological consideration, ACE inhibitors have been shown to decrease the latency of the swallow re ﬂ ex, to increase the involuntary swallow frequency and to protect patients from nocturnal aspirations [500 e 502] . The subsequent and clinically most relevant question whether ACE inhibitors also reduce the incidence of aspiration pneumonia has no clear answer to date. A recent meta-analysis including 5 multicenter RCTs, 8 cohort and nested-case control studies and 6 case e control studies points towards a protective role of ACE inhibitors in this context [503] . However, a very recent multicenter RCT randomizing tube-fed poststroke patients to $2.5\,\mathrm{\meg}$ Lisinopril or placebo was prematurely terminated because of an excess of mortality in the intervention group. There was no difference in the incidence of pneumonia [504] . See supplementary data for Clinical Questions 38 e 41 .

Funding

This work was supported by the ESPEN.

Con ﬂ ict of Interest

The expert members of the working group were accredited by the ESPEN Guidelines Group, the ESPEN Education and Clinical

Practice Committee, and the ESPEN executive. All expert members have declared their individual con ﬂ icts of interest according to the rules of the International Committee of Medical Journal Editors (ICMJE). If potential con ﬂ icts were indicated, they were reviewed by the ESPEN guideline of ﬁ cers and, in cases of doubts, by the ESPEN executive. None of the expert panel had to be excluded from the working group or from co-authorship because of serious con ﬂ icts. The con ﬂ ict of interest forms are stored at the ESPEN guideline of ﬁ ce and can be reviewed by ESPEN members with legitimate interest upon request to the ESPEN executive.

Abbreviations

ALS Amyotrophic Lateral Sclerosis ALSFRS Amyotrophic Lateral Sclerosis functional rating scale ALSFRS-R Amyotrophic Lateral Sclerosis functional rating scale revised ALSSS Amyotrophic Lateral Sclerosis swallowing severity scale BIA bioelectrical impedance BMD bone mineral density BMI body mass index CBA clinical bedside assessment CNS central nervous system DBS deep brain stimulation DEXA dual-energy X ray absortiometry DHA docosahexaenoic acid DYMUS Dysphagia in multiple sclerosis EAT-10 eating assessment tool EDSS expanded disability status scale EMST expiratory muscle strength training EN enteral nutrition EPA eicosapentaenoic acid FEES Fiberoptic endoscopic evaluation of swallowing FFM free fatty mass FM fat mass FOOD feed or ordinary food FVC forced vital capacity LOS length of stay MDT-PD Munich dysphagia test-Parkinson's disease MNA mini-nutritional assessment MND motor neuron disease MRI magnetic resonance imaging MS multiple sclerosis MUST malnutrition universal screening tool OD oropharyngeal dysphagia ONS oral nutritional supplementation PA phase angle PD Parkinson's disease PEG percutaneous endoscopic gastrostomy PN parenteral nutrition PUFA poly-unsaturated fatty acids QoL quality of life RCT randomized controlled study REE resting energy expenditure RIG radiologically inserted gastrostomy SDQ swallowing disturbance questionnaire TEE total energy expenditure TRPV1 transient receptor potential cation channel subfamily V member 1 VAST video-assisted swallowing therapy VFM video ﬂ uoromanometry VFS video- ﬂ uoroscopy VVST volume-viscosity swallow test WL weight loss

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Appendix A. Supplementary data

Supplementary data related to this article can be found at https://doi.org/10.1016/j.clnu.2017.09.003 .

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表 1
1++	High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias.
	High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias.
1+	Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort studies.
	Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias. Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort studies.
2++
	High quality systematic reviews of case control or cohort studies. High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is

ＺIT	Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

N	Case control or cohort studies with a high risk of confounding or
	bias and a significant risk that the relationship is not causal
	Non-analytic studies, e.g. case reports, case series
	Expert opinion

表 2
a. Grades of recommendation
	At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or

	A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

	A body of evidence including studies rated as 2++, directly applicable to the target population; or
	A body of evidence including studies rated as 2+, directly applicable to the target population, and demonstrating overall consistency of results; O1
	O1 Extrapolated evidence from studies rated as 1++ or 1+ Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2++ or 2+ Good practice points/expert consensus: Recommended best practice based on the clinical experience of the guideline development group
GPP
GPP
b. Forms of recommendation
Judgment	Judgment
Undesirable consequences clearly outweigh desirable consequences	Strong recommendation against

Undesirable consequences probably outweigh desirable	Conditional recommendation against
consequences
Balance between desirable and		Recommendation for research and possibly conditional
	undesirable consequences is
closely balanced or uncertain	recommendation for use restricted to trials
	Conditional recommendation for
Desirable consequences probably outweigh undesirable consequences
Desirable consequences clearly outweigh undesirable	Strong recommendation for

consequences

引用 / 出处

2017 ESPEN指南：神经病学临床营养. 2017.